Monthly research review: February 2020

~ Simon

 

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during February 2020.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 

So, what happened during February 2020?

In world news:

February 5th – A research team in Hong Kong announced the development of a droplet-based electricity generator, which will allow electrical energy production with the minimum possible use of water (Click here to read more about this).

February 9th – Storm Ciara battered the UK.

 

February 12th – Researchers discovered a new group of antibiotics that display a unique approach to attacking bacteria, providing a promising new approach in the fight against antimicrobial resistance (Click here to read more about this).

February 24th – Michael Jordon’s tribute to the late Kobe Bryant almost made me cry (almost!). It’s a beautiful speech for a basketball fan.

 

February 26th – Astronomers announced that Earth had acquired a second, slightly smaller moon. Designated 2020 CD3, a calculation of its orbit suggests that it has been orbiting Earth for approximately 3 years. But given that it is the size of a car, don’t expect a second moon landing any time soon (Click here to read more about this).

In the world of Parkinson’s research, a great deal of new research and news was reported:

In February 2020, there were 921research articles added to the Pubmed website with the tag word “Parkinson’s” attached (1803for all of 2020 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. ApoE4 influences alpha synuclein pathology

Two papers published back-to-back this month suggesting that apolipoprotein E4 (APOE4) genotype, a major risk factor for neurodegenerative diseases, can affect α-synuclein pathology in mouse models & cases of α-synucleinopathy, like Parkinson’s. The first paper used mouse models of α-synucleinopathy & analyzed cognition in patients with Parkinson’s to demonstrate that APOE4 directly regulates α-synuclein pathology & is associated with faster cognitive decline (in 2 separate cohorts –  to read this paper). And the second study also generated a mouse model of α-synucleinopathy & reported that APOE4 (but not APOE2 or APOE3) exacerbated Parkinson’s-associated α-synuclein pathology… independent of amyloid ( to read more about this, click here to read the press release, and click here to read the SoPD post on this topic).

2. UDCA study results

Researchers have published the results of an open‐label, prospective, multiple‐ascending‐dose study of oral Ursodeoxycholic acid (UDCA) in 5 people with Parkinson’s. The results suggest that the drug is safe and well tolerated in people with Parkinson’s. The treatment also resulted in modest increases in ATP (energy) levels (based on brain imaging techniques). The investigators concluded that the “findings warrant additional studies” ( to read more about this and click here to read a SoPD post on the topic).

3. Differentiating PD from MSA

researchers report that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from cases of Parkinson’s & samples from cases of multiple system (MSA) atrophy (sensitivity of 95.4%). “These findings suggest that α-synuclein aggregates that are associated with Parkinson’s & multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified & detected by α-synuclein-PMCA”. “The properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain”. This “may also enable the development of a biochemical assay to discriminate between Parkinson’s & multiple system atrophy” ( to read more about this, click here to read the editorial, click here to read the press release, and click here to read an SoPD post on this topic).

4. Making Lewy bodies in cell culture

Lewy bodies are one of the pathological hallmarks of Parkinson’s and associated conditions. This month, Swiss researchers published data demonstrating the formation of Lewy bodies in cell culture. The model allowed the investigators to dissect specific biological events associated with each stage of Lewy body formation, as well as how they may be contributing to the neuronal dysfunctions and degeneration onbserved in conditions like Parkinson’s ( to read more about this).

 

5. The CDNA clinical trial topline results

Biotech firm Herantis Pharma announced topline results of Phase 1-2 CDNF clinical trial in Parkinson’s. Confirms positive safety & tolerability of CDNF in advanced-PD, + encouraging PET imaging in some patients. Final results are expected in Q3 2020. CDNF is “Cerebral dopamine neurotrophic factor”, considered a neurotrophic factor though it functions differently to other NFs like GDNF. This study has involved implantation of tubes into the brain & monthly delivery of CDNF for 6+6 months. “We have initiated the planning for a Phase 2 study with a longer treatment period that will assess the efficacy of CDNF in earlier-stage, well-characterized Parkinson’s patients. We currently expect to initiate patient enrolment in 2021” ( to read the press release and click here to read a SoPD post on this topic).

 

 

6. The CPT & VAI agreement

Admittedly I am slightly biased here, but I thought this was exciting news – The Cure Parkinson’s Trust and Van Andel Institute announced a new three-year co-funding agreement that pledges USD$4.5 million to further Parkinson’s research, strengthening an already long-standing partnership ( to read more about this).

 

Basic biology news

  • Embryonic ablation of Mesencephalic astrocyte-derived neurotrophic factor (MANF) causes prolonged activation of the unfolded protein response, but does NOT cause the loss of midbrain dopamine neurons in mice ( to read more about this).
  • OTU deubiquitinase ubiquitin aldehyde binding 1 (OTUB1) – a deubiquitinating enzyme – has been associated with Parkinson’s & Alzheimer’s. New study suggests OTUB1 may contribute to lewy body pathology through its amyloidogenic properties ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting a conserved mechanistic link btween autophagy & NAD(H) metabolism. Proposes boosting NAD(H) levels may be an effective intervention for conditions associated with autophagy dysfunction ( to read more about this).
  • Researchers provide experimental evidence suggesting the direct involvement of various forms of truncated forms of Parkinson’s-associated alpha synuclein in differential seeding activities; might be relevant for differential strain formation & fate ( to read more about this).

  • Researchers report that inflammation-associated NLRP3 is modified by acetylation in macrophages & is deacetylated by SIRT2. Dysregulation of this acetylation switch could be the origin of aging-associated chronic inflammation ( to read more about this and click here to read the press release).
  • Researchers have a bioRxiv manuscript suggesting the structures of α-synuclein filaments extracted from multiple system atrophy (MSA) brains differs from those formed in vitro using recombinant proteins. Important implications for understanding the mechanisms of aggregate propagation & neurodegeneration in human brain, as well as a cautionary note about interpreting findings/conclusions from studies using synthetic assemblies ( to read more about this).
  • Cholinesterase inhibitor, Rivastigmine, modifies the α-secretase pathway & potentially early Alzheimer’s. It “can modify the levels of several shedding proteins & directs APP processing toward the non-amyloidogenic pathway” ( to read more about this).
  • Researchers present “a universal kinetic model for biofilament formation in which every fundamental process in the reaction network can be catalytic”. Works for Alzheimer’s-associated β-amyloid, what about Parkinson’s proteins? ( to read more about this).
  • Researchers present a cell-penetrating peptide that targets Alzheimer’s-associated beta-amyloid (Aβ), which stabilises Aβ in a non-amyloid state & inhibits Aβ-induced neurotoxicity ( to read more about this).

  • Further evidence suggesting cross talk between Alzheimer’s-associated amyloid-beta peptides & Parkinson’s-associated alpha-synuclein. “Significantly increased aggregation propensity of α-synuclein in the presence of minor concentrations of Aβ” (in vitro – to read more about this).
  • Researchers have a bioRxiv manuscript outlining a multi-method approach to integrate gene expression & SNP level data to identify credible actionable genes for general cognitive ability (16 druggable targets identified – to read more about this).
  • Researchers report that the motor-stimulating effect of methylphenidate can be positively fostered in the presence of α-synuclein/Synapsin III co-aggregation. Implications for Parkinson’s? ( to read more about this).
  • Researchers report a high-throughput assay to quantify the stability of amyloid fibrils (lysozyme, insulin & Parkinson’s-associated α-synuclein) that can be extended to different amyloid species (Click here to read more about this).
  • Researchers suggest that size-dependent characterization of Parkinson’s-associated alpha-synuclein aggregates may influence their toxicity (Click here to read more about this).
  • Researchers provides evidence that mitochondria seed the aggregation of Parkinson’s-associated α-synuclein in neurons. Mitochondrial stress (in the form of enhanced ROS production) is a major trigger for oligomerization ( to read more about this).

  • Researchers propose a mechanism of Parkinson’s-associated alpha synuclein translocation into mitochondria, via Voltage-Dependent Anion Channel (VDAC), an outer mitochondrial membrane protein (each isoform of VDAC was studied using knock downs – to read more about this).
  • RT-QuIC detection of alpha synuclein seeding activity in dementia with lewy bodies patient brains and synuclein transgenic mice. Small step towards a biomarker? ( to read more about this).
  • Researchers present the maturation of the human striatal dopamine system (as revealed by PET & quantitative MRI – to read more about this).
  • Researchers conducted a genome-wide synthetic genetic interaction array to identify toxicity modifiers of Aβ42, using yeast. They report flavin mononucleotide (produced from riboflavin/vitamin B2) reduces Aβ42 toxicity ( to read more about this).
  • Researchers report a structural & mechanistic model for the interaction of Parkinson’s-associated LRRK2 with microtubules. Broad implications for the design of therapeutic LRRK2 kinase inhibitors ( to read more about this).
  • DNA from various, unrelated gram-positive & gram-negative bacteria results in a more pronounced TAU misfolding compared to eukaryotic DNA. Could microbial DNA may play a role in propagation of protein misfolding in Parkinson’s & Alzheimer’s pathogenesis? ( to read more about this).

  • Researchers have a bioRxiv manuscript suggesting new mechanisms to explain GABA-A receptor modulation of dopamine release & providing new insights into the actions of benzodiazepines within the striatum ( to read more about this).
  • Researchers report that the Dopamine D5 receptor can modulate L-DOPA induced dyskinesia in models of Parkinson’s & is a critical activator of cholinergic interneurons (via pERK and pS6 – to read more about this).
  • Researchers report that monoubiquitination of VDAC1 (a critical substrate of PARKIN) plays important roles in the pathologies of Parkinson’s by controlling apoptosis (in flies at least –  to read more about this).
  • Researchers report that an amphipathic model peptide conjugated with Rasagiline reduces Parkinson’s-associated α-syn aggregation (in vitro – to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that besides classical ThT positive products, α-syn fibrillization in saline gives rise to competing fibril polymorphs that are invisible to ThT (“stealth polymorphs” – to read more about this).
  • Researchers report that the STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/Parkin or mtDNA mutator models. Is it just a mammalian thing? ( to read more about this).
  • Macrophages transfer mitochondria to neurons?!? Researchers have a bioRxiv manuscript suggests that to resolve pain, macrophages can transfer mitochondria to sensory neurons. A novel mechanism for resolution of inflammatory pain ( to read more about this).

  • Researchers report evidence linking a physiological role for Parkinson’s-associated α-synuclein in the regulation of retinoic acid-mediated gene transcription & its toxicity in the synucleinopathies ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that the product of gut bacterial degradation of unabsorbed residues of levodopa in fecal samples may impact intestinal motility in people with Parkinson’s ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that α-synuclein expression in Parkinson’s is controlled by SNCA′s histone posttranslational modifications & modulation of the histone landscape of SNCA reduces α-synuclein expression ( to read more about this).
  • Parkinson’s-associated LRRK2 maintains mitochondrial homeostasis & regulates the innate immune system response to mycobacterium tuberculosis. Altered innate immune gene expression in Lrrk2 KO macrophages is driven by a combination of mitochondrial stresses ( to read more about this).
  • Researchers report that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated ubiquitin-proteasome dysfunction, prior to onset of behavioural & neurodeg. issues in model of Parkinson’s ( to read more about this).
  • Mitochondrial ATP synthesis is reduced in familial Alzheimer’s models (due to reduced mitochondrial pyruvate oxidation). Pharmacological GSK-3β inhibition improves mitochondrial ATP synthesis & respiration ( to read more about this).

  • Researchers report a marked neurotoxic potential of cobalt‐based (but not tungsten carbide) nanoparticles, & show that neuronal cell death may occur through a ferroptosis‐like mechanism ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting novel insights into oxidative CaMKII-CaM dysfunction, which may contribute to the pathophysiology of Parkinson’s ( to read more about this).
  • Researchers present 3D nanoscaffolds to aid our understanding of the molecular basis of Parkinson’s mimetic-induced Parkinsonism & the discovery of neuroprotective agents ( to read more about this).
  • Researchers report that astrocytic dopamine D2 receptor regulates glutathione synthesis (via PKM2-mediated Nrf2 transactivation). Also, pyridoxine (vitamin B₆) induces glutathione synthesis (via dimerizing with PKM2) & rescues model of Parkinson’s ( to read more about this).
  • New research finds inoculation of α-Syn preformed fibrils into stellate & celiac ganglia induces spreading of α-Syn pathology (via the autonomic pathway) to both the CNS & the autonomic innervation of peripheral organs bidirectionally (in transgenic mice – to read more about this).
  • Researchers report evidence that cholesterol modulates the clustering of synaptic vesicles induced by alpha syn & supports the role of the disorder-to-order equilibrium of the NAC region in the modulation of the alpha syn ( to read more about this).

  • Diabetic mice apparently suffer cognitive decline. But Chinese researchers report that a 28-day intermittent fasting regimen improves this (via a microbiota-metabolites-brain axis). Interestingly, dministration of TUCDA has a similar effect to intermittent fasting ( to read more about this).
  • Researchers report that PARKIN-coregulated gene (PACRG) plays no role in mitophagy, but does promote NF-κB signaling downstream of TNFR1. PACRG is recruited & protects cells by stabilizing ‘linear ubiquitin chain assembly complex’ (LUBAC – to read more about this and click here to read the press release).
  • Researchers report a novel role of the NLRP3-IL-1β signaling pathway in gauging the severity of sepsis-associated inflammation & determining whether acute neuroinflammation will resolve or transition to low grade chronic neuroinflammation ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting oxidation of Parkinson’s-associated PARKIN (considered a loss-of-function event) actually has 3 protective effects in adult midbrain: H2O2 reduction, dopamine radical conjugation, & neuromelanin formation ( to read more about this).
  • Researchers present data suggesting that C/EBPβ/δ-secretase signaling mediates Parkinson’s pathogenesis (via regulating the expression & cleavage of α-Syn & MAO-B – to read more about this).
  • Researchers report that Parkinson’s-associated Leucine-rich repeat kinase 2 (LRRK2) modulates nuclear morphology & genomic stability in striatal projection neurons during aging ( to read more about this).

  • Researchers report that deficiency in the Parkinson’s-associated protein DJ-1 promotes intestinal epithelial cell apoptosis & aggravates inflammatory bowel disease (via p53). Pharmacological inhibition of p53 relieved inflammation in DJ-1-/- mice ( to read more about this).
  • Researchers report a high-throughput screen of small molecule that identifies modulators of mitochondrial function in neurons. Strikingly, local anesthetics, estrogen agonists, isoflavones & tricyclic antidepressants get highlighted ( to read more about this).
  • Researchers report the influence that the tail of the ventral tegmental area exerts on the rodent dopamine system, modulating the motor & non-motor symptoms related to a partial loss of dopamine neurons in a model of Parkinson’s ( to read more about this).
  • Researchers collecting RNA-seq data from Parkinson’s-associated brain regions from 117 human brains, & applied a bank of 5 transcriptome quantification methods to find significant variation among expression quantitative trait loci classes. Expression quantitative trait loci are genomic loci that explain variation in expression levels of mRNAs. These results demonstrate the importance of capturing information on the regulation of known & novel splicing for the understanding of complex brain disorders. And the authors have released the rich resource of data generated in this study via a ( to read more about this).
  • MitoBlue is a synthetic bisbenzamidine derivative that stains mitochondria with high specificity through a still undetermined mechanism. Researchers report its utility in analysing mitochondria-lysosome communication ( to read more about this).

  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated LRRK-G2019S variant alters the magnitude & direction of behavioral responses to stress (in mice –  to read more about this).
  • Researchers report that intrinsic levels of regulation of protein aggregation in the healthy state are correlated with the selective vulnerability of cells & tissues to protein misfolding diseases ( to read more about this).
  • Researchers have a bioRxiv manuscript presenting directed transcript editing of a pathological mutation in a mouse model of the neurodevelopmental disease, Rett syndrome ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated Parkin, autophagic receptors & the Golgi complex orchestrate mitochondrial lipid remodeling to execute robust mitophagy ( to read more about this).
  • Researchers report that human insulin modulates α-synuclein aggregation (via DAF-2/DAF-16 signalling pathway) in C. elegans model of Parkinson’s ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that long-term nicotine exposure alters the trafficking of α4β2-type nicotinic acetylcholine receptors (α4β2Rs) by dispersing & redistributing the Golgi apparatus ( to read more about this).

 

 

Disease mechanism

  • Researchers report that deletion of Autophagy related 5 (Atg5 – a key player in autophagy) in microglia causes Parkinson’s-like symptoms & loss of dopamine neurons in mice, via NLRP3 inflammasome activation. NLRP3 inhibitor MCC950 rescued situation (Click here to read more about this).

  • Researchers have a bioRxiv manuscript suggesting that synergistic IFN-γ/LRRK2 activation serves as a direct link between inflammation & neurodegeneration in Parkinson’s. “IFN-γmay serve as the central regulator of LRRK2-mediated responses during infections & immunity, as well as neuroinflammatory processes in a cell-type specific manner” ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting a sexually dimorphic inflammatory response to chronic MPTP treatment in primates; males may have higher vulnerability than females; XPro1595 shitfts peripheral & central inflammation ( to read more about this).
  • Researchers have a bioRxiv suggesting that developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity & motor deficits ( to read more about this).
  • Researchers report that the Parkinson’s-associated α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure ( to read more about this).
  • Researchers present KKPA4026, a potent Nrf2 activator via interference with Keap1-Nrf2 interaction. KKPA4026 effectively rescued Parkinson’s-like behavioral deficits & protected dopaminergic neurons in MPTP mouse model (Click here to read more about this).
  • Meta analysis suggests patients with various bacterial, viral, & fungal infections (Helicobacter pylori, hepatitis C virus, Malassezia, & pneumoniae) might have increased risk of Parkinson’s. Antiviral treatment of HCV could reduce the risk of PD ( to read more about this).

  • Researchers present data supporting the involvement of non‐cell‐autonomous mechanisms contributing to the pathogenesis of GBA1‐associated Parkinson’s, & identify new opportunities to correct these changes with pharmacological intervention. They report that lysosomal & inflammatory defects in GBA1‐mutant astrocytes are normalized (to different extents) by LRRK2 inhibition, providing further evidence for functional intracellular crosstalk between GCase & LRRK2 activities (Click here to read more about this).
  • Researchers report chronic infiltration of T-cells in the brain in a non-human primate model of Parkinson’s (MPTP). They saw chronic normalization of serum RANTES & altered microglial morphology at 48 weeks (post MPTP – to read more about this).
  • New data suggests “that under physiological conditions, α-syn associates with membranes via the NAC region, & that too much α-syn perturbs axonal transport via aggregate formation, instigating synaptic & behavioral defects seen in Parkinson’s” ( to read more about this).
  • Researchers report a potential role for Ten-Eleven Translocation 2 (TET2) in Parkinson’s, via the CDKN2A activity-dependent epigenetic pathway. Knockdown of Tet2 expression in the substantia nigra of MPTP-induced PD mice rescued phenotype (via p16 – to read more about this).
  • Researchers report that transplanting dopamine neurons into a glial cell line-derived neurotrophic factor (GDNF)-rich host brain supports neuronal survival (BUT impedes plasticity) in models of Parkinson’s. “Delayed exposure to GDNF promoted functional recovery through increases in DAn specification, DAn plasticity, & DA metabolism”. “Results demonstrate the potential of neurotrophic gene therapy strategies to improve graft outcomes” ( to read more about this).

  • Researchers present in-depth phenotyping & focussed assessment of putative neuroprotective compounds taking us closer to disease stratification & precision medicine in Parkinson’s ( to read more about this).
  • Researchers present NLX-112 – a highly selective serotonin 5-HT1A receptor agonist – which exhibits anti-Parkinson’s & reduces L-dopa induced dyskinesias without impairing therapeutic activity in marmosets ( to read more about this).
  • Researchers report gastrointestinal & enteric nervous system issues following inoculation of the duodenal wall of mice with α-syn preformed fibrils. Aged mice (but not young) exhibit Parkinson’s features ( to read more about this).
  • Researchers report that TFEB-mediated autophagy activation in Parkinson’s models plays an important role in compensatory protection, & that these protective effects can be increased with autophagy enhancers (TFEB enhancers Torin 1 & C1 – to read more about this).
  • Azoramide – a small-molecule modulator of the unfolded protein response with antidiabetic activity – protects iPSC-derived dopamine neurons carrying the Parkinson’s-associated PLA2G6-D331Y mutation through restoring ER function & CREB signaling ( to read more about this).
  • In vitro introduction of Parkinson’s-associated LRRK2 G2019S (via CRISPR/Cas9 edit) into marmoset ES & IPS cells resulted in elevated kinase activity. Differentiation into dopamine neurons resulted in increased ROS, decreased viability, & reduced neurites ( to read more about this).

  • Researchers colleagues have a bioRxiv manuscript presenting a high throughput screening assay that has highlighted metformin, enasidenib, nitisinone, felodipine, & ethosuximide as repurposable drugs in a c.elegans model of Parkinson’s ( to read more about this).
  • The same researchers have another bioRxiv manuscript suggesting that Parkinson’s may originate as a metabolic disorder, & (again) highlight metformin as a potential new drug candidate for repurposing to PD ( to read more about this).
  • Researchers present 2 novel 1-hydroxypyridin-2-one metal chelators that prevent & rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s ( to read more about this).
  • Researchers report progranulin as a lysosomal Parkinson’s-associated protein that is downregulated by α synuclein aggregates in microglia – a novel disease mechanism for PD? ( to read more about this).
  • Researchers discover many long non-coding RNAs dysregulated in Parkinson’s postmortem brain samples (using a lncRNA‐focused analysis approach). They highlight LINC‐PINT, NEAT1, & RMST, & propose a potential neuroprotective role for LINC-PINT ( to read more about this).
  • Researchers have a bioRxiv manuscript providing further experimental evidence that T cells play a role in α-synucleinopathies (like Parkinson’s). Immunocompromised mice have increased α-syn pathology in the sub. nigra ( to read more about this).
  • Researchers developed & characterized an inducible Dicer conditional knockout (DAT promoter) mouse model of Parkinson’s. Plus, they validated the antiparkinsonian effects of a sigma-1 receptor agonist & protective effects of dihydromyricetin ( to read more about this).

 

Clinical research

  • A case study of an individual with Parkinson’s who was transplanted (at age 49yrs) with fetal tissue reports the co-existence of Tau & α-synuclein pathology in the grafted cells at autopsy (at age 70yrs)… but only in the left-side graft?!? (Click here to read more about this).
  • Polish researchers report impact of subthalamic-deep brain stimulation on UPDRS III OFF score & cognitive alterations suggest a neuromodulatory role (mainly during the first 9–18 months after surgery – click here to read more about this).

  • Researchers assessed changes in peripheral innate immune markers in 41 cases of Parkinson’s (23 high risk of early dementia & 18 low risk). Monocytes were up in PD vs control; plus elevated serum bacterial endotoxin, mainly in high risk group. Interesting: “bacterial translocation associated changes may contribute towards progression to Parkinson’s dementia” – potential biomarker? ( to read more about this).
  • Michael J Fox Foundation lead a consortium that has published a report on foundational data to inform the integration of pS935 & total LRRK2 levels as biomarkers in therapeutic trials of Parkinson’s-focused LRRK2 kinase inhibitors ( to read more about this).

  • Researchers have a bioRxiv manuscript suggesting, in two independent progressive supranuclear palsy (PSP) cohorts, common variations at the Parkinson’s-associated LRRK2 locus determine survival from motor symptom onset to death ( to read more about this).
  • More epidemiological research suggesting “The apparent association of β2 agonists with a decreased risk of Parkinson’s is likely the result of reverse causality rather than a biological effect of these drugs on the risk of PD” But what about the preclinical data?!? ( to read more about this).
  • New research involving high-res PET brain imaging reveals subtle impairment of the serotonin transporter in an early non-depressed Parkinson’s cohort, suggesting a relative preservation of SERT in early non-depressed PD patients (vs controls – to read more about this).
  • Researchers report that Lewy body pathology with Parkinsonisms can occur within the context of the lysosomal storage disorder Fabry disease. N=1 out of 2 analysed cases, but interesting observation. Larger Fabry disease cohort required ( to read more about this).
  • Researchers lead a next-gen sequencing study reporting the identification of novel variants in candidate genes for Parkinson’s in black South African & Nigerian patients. Small study, but interesting results ( to read more about this).

  • Researchers screened the GBA gene in a small cohort (n=30) of black South African people with Parkinson’s. 8 variants were found in 17 individuals (including p.R120W in one person diagnosed at 35yrs – to read more about this).
  • Researchers report a 4-year longitudinal study of motor & non-motor symptoms in 133 LRRK2-variant Parkinson’s cases (& 69 non-variant carrying PD cases – click here to read more about this).
  • Researchers report direct activation of primary motor cortex during subthalamic, but not pallidal deep brain stimulation in primate models of Parkinson’s ( to read more about this).
  • Researchers report an average 49% reduction of pigmented neurons in the locus coeruleus – a major source of major source of noradrenaline in the brain – of people with progressive supranuclear palsy (PSP) vs controls ( to read more about this).
  • Researchers report evidence of previously undetected α-synuclein oligomers in the autonomic nervous system of the skin & propose their quantitative analysis as potential biomarker for Parkinson’s. They conducted a comparative proximity ligation assay analysis in a cohort (n=57) of Parkinson’s patients including a subgroup of monozygotic twins discordant for PD (n=19 couples), vs 29 controls. PLA scores enabled the distinction between PD patients & healthy subjects but no association was reported between PLA score & clinical features of Parkinson’s, including duration, UPDRS part II & III scores, H&Y stage, & constipation. “Taken as a whole, the present cross-sectional study design does not enable us to infer a cause-effect relationship between PLA-staining & neuronal synaptic density & clinical features. Therefore, the present results should be interpreted cautiously as the hypothesis of a putative toxic effect of α-synuclein oligomers needs to be addressed in a prospective study” ( to read more about this).
  • Researchers present a longitudinal case-control study (12 months+) of spirituality & faith in 42 people with Parkinson’s (& 39 controls). PD is not associated with a decline in religious faith or spirituality ( to read more about this).

  • Researchers report that neuropsychiatric symptoms are significantly associated with poorer quality of life, even in early Parkinson’s. Early screening may allow for delivery of better support & treatment to patients & families ( to read more about this).
  • Researchers have a new bioRxiv manuscript presenting a freely available probabilistic atlas & MRI dataset of the human locus coeruleus for researchers to use to facilitate accurate better localisation ( to read more about this).
  • Researchers report that levels of Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) are significantly elevated in the substantia nigra of people with Progressive Supranuclear Palsy (PSP). Also +vely correlated with hyperphosphorylated tau (Click here to read more about this).
  • The Superior Colliculus Study Group suggest that pathological superior colliculus visual responses in de novo Parkinson’s are present early on the course of the condition – could imaging of the superior colliculus highlight preclinical biomarkers? (Click here to read more about this).
  • Small study, but sig. increase in the severity of Lewy body pathology observed in postmortem brains from people with Parkinson’s + nonamnestic mild cognitive impairment (vs PD + amnestic MCI). Overall considerable heterogeneity within PD‐MCI pathology (Click here to read more about this).
  • Researchers report that bursts of low frequency activity in the subthalamic nucleus may restrict the overall capacity of the system to encode physiologically relevant information about intended actions in Parkinson’s ( to read more about this).
  • Small study, but French researchers report that ‘REM sleep without atonia‘ increased significantly at follow-up in a longitudinal sleep study of Parkinson’s in patients with REM sleep behaviour disorder (Click here to read more about this).

  • Researchers conducted longitudinal Fluorodopa PET brain imaging of dopamine synthesis in 57 homozygous & heterozygous GBA1 variant carriers (15 with Parkinson’s) & 98 non-carrier controls (Click here to read more about this).
  • Researchers quantified 341 proteins in 2 independent cohorts to identify Parkinson’s-relevant cerebrospinal fluid biomarkers. They found granin family proteins are reduced in PD, suggesting a possible mechanism for monoamine transmission reduction. “The continuous development of robust platforms to quantify small changes in proteins in biospecimens as well as the evaluation of larger longitudinal cohorts are critical for future patient subtyping & evaluation of therapeutics” ( to read more about this).
  • Researchers report elevated serum levels of Parkinson’s-associated α-synuclein in Huntington’s disease patients (vs. controls). No difference in levels between symptomatic vs. premanifest (Click here to read more about this).
  • Researchers present data questioning the role for rare heterozygous or bi-allelic VPS13C mutations in late onset Parkinson’s ( to read more about this).
  • Researchers report that exercise (1 h 2x per week for 12 weeks) may improve movement & balance in people with Parkinson’s by reversing the upregulated T-cell activation pathways associated with PD ( to read more about this).
  • New bioRxiv manuscript suggests that peripheral blood cells are NOT a suitable biosample for analysis of PINK1 – Parkin mitophagy function in Parkinson’s patients ( to read more about this).

  • Researchers conducted a prospective observational design, to determine whether long-distance skiers in Swedish (n = 197,685) have a reduced incidence of Parkinson’s compared to matched controls (n = 197,684) during 21 years of follow-up. The results suggest that: “A physical active lifestyle is associated with reduced risk for Parkinson’s. This association weakens with time and might be explained by a motor reserve among the physically active” ( to read more about this).
  • Researchers report that nonmercaptalbumin (the directly oxidized form of human serum albumin) is significantly elevated in idiopathic Parkinson’s & PARK2 patients compared with controls, regardless of disease course & severity ( to read more about this).
  • Researchers present the results of a single-blinded, randomized controlled trial testing the efficacy of bladder training for troublesome lower urinary tract symptoms in Parkinson’s. Results look promising, but requires larger replication ( to read more about this).
  • Researchers report a relative preservation of mind-wandering in Parkinson’s patients who experience visual hallucinations, which is associated with increased visual cortex-default network coupling ( to read more about this).
  • Researchers report that “degeneration of nigrostriatal fibres functionally impairs distinct striatocortical connections, disturbing the efficient interplay between motor processing areas & impairing motor control in patients with Parkinson’s” (Click here to read more about this).
  • Small study, but researcher analysed whole-exome sequencing data of 340 Parkinson’s cases & 146 matched controls from the Michael J Fox supported PPMI database & observed a significant exome-wide burden of singleton loss-of-function variants ( to read more about this).

  • Researchers quantified circulating cell-free mitochondrial DNA in cerebrospinal fluid samples from 372 Parkinson’s patients & 159 matched controls (from the Michael J Fox foundation supported PPMI dataset) at 2 time points. They found that ccf-mtDNA levels appear sig. reduced in Parkinson’s (vs matched controls) & are associated with cognitive impairment. Their data suggest that this reduction in ccf-mtDNA is associated with the commencement, type & duration of treatment ( to read more about this).
  • And yet more PPMI data!!! Clinical & DATscan brain imaging characteristics of LRRK2-associated & GBA-associated Parkinson’s participants in the PPMI study confirms milder phenotype associated with LRRK2‐PD, but does not find more aggressive phenotype in N370 GBA‐PD. “Longitudinal data will be essential to define the slope of progression for both genetic cohorts” ( to read more about this).
  • Researchers report results of the “EXosomes in PArkiNsons Disease” (EXPAND) study suggesting that in-depth analysis of extracellular vesicle trafficking may allow for new biomarkers 4 PD & possible targets for personalized interventions ( to read more about this).
  • Researchers have a bioRxiv in which they used UK Biobank data to reproduce several well-known associations with Parkinson’s, plus shown effect of diabetes on PD risk is modified by a PD genetic risk score ( to read more about this).

  • Researchers highlight differing characteristics of corticomuscular control of walking in the young, the elderly, & people with Parkinson’s ( to read more about this).
  • Researchers report evalated soluble triggering receptor expressed on myeloid cells 2 (TREM2) in a subgroup of people with Parkinson’s with increased level of Tau in their cerebrospinal fluid, but not in PD subgroups with a positive CSF amyloid-β biomarker signature (Click here to read more about this).
  • New research finds clear separation of Alzheimer’s/dementia with Lewy bodies subjects from Alzheimer’s (without LBs) & the cognitively normal, based on cardiac tyrosine hydroxylase fibre density ( to read more about this).
  • Researchers have a medrxiv manuscript suggesting that mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene do not have a major role in REM-sleep behavior disorder. SMPD1 variants have been associated with Parkinson’s & DLB ( to read more about this).
  • UK Parkinson’s Pain Study group reports the results of first genome‐wide association study of pain in PD (898 PD subjects with pain vs 420 PD without pain). Their results suggest TRPM8 as a risk factor ( to read more about this).
  • Researchers present the discrimination of progressive supranuclear palsy (PSP) from Parkinson’s disease (using wearable technology & machine learning – click here to read more about this).
  • A nationwide, population-based case-control study, involving all US incident Parkinson’s cases (N = 89,790) & all comparable controls (N = 21,549,400) finds use of well water was inversely associated with PD risk (OR = 0.87, 95% CI 0.85–0.89). “There was little evidence that well water use increased risk of Parkinson’s in any individual state” ( to read more about this).

  • Researchers report that memory deficits in Parkinson’s are associated with reduced beta power modulation. Longer disease duration was correlated with a larger reduction in beta modulation during encoding ( to read more about this).
  • Researchers present the results of a pilot study exploring passive monitoring of Parkinson’s at home using a passive radio-wave-based home monitor ( to read more about this).
  • Researchers also present the results of a pilot study in clinic & home setting of multiple wearable sensors on individuals with Parkinson’s & Huntington’s disease. Approach was “feasible & well-received”…”Sensors can identify statistically sig. differences in activity profiles between individuals with movement disorders & those without”…”continuous, objective monitoring can reveal disease characteristics not observed in clinic” ( to read more about this).
  • Researchers report specific white matter tract degeneration affecting posterior thalamic tracts in people with Parkinson’s who have hallucinations & low visual performance (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that continuous force measurements reveal no inhibitory control deficits in Parkinson’s ( to read more about this).
  • Researchers report a self-administered, tablet-Based application that can reliably distinguish between OFF & ON states in fluctuating Parkinson’s ( to read more about this).

  • Researchers report a comparison of indirect & direct targeted subthalamic deep brain stimulation in the treatment of Parkinson’s, taking into account surgical method & clinical outcome over a 15-year timespan ( to read more about this).
  • The choroid plexus plays a major role in cerebrospinal fluid production. Researchers reports negative associations between choroid plexus volume & CSF proteins, which was lower in late mild cognitive impairment & Alzheimer’s. Begs the question: Do we need to account for the choroid plexus volume in future studies of CSF-based biomarkers? (Click here to read more about this).

 

New clinical trials

  • New clinical trial registered: Korea-based Peptron, Inc is initiating Phase 2a clinical testing of their slow release version of Exenatide called PT320, assessing safety/tolerability in early Parkinson’s. 3 arms, 2 doses, 99 participants, reporting 2022 (Click here to read more about this).

  • New clinical trial registered: The “Intranasal Insulin in Parkinson’s” (INI-PD) study will be a randomised, double blind, multi-arm study following 30 people for 3 weeks of different doses to intranasal insulin. 1st outcome = Safety & tolerability ( to read more about this).
  • New clinical trial registered exploring near infrared endoventricular illumination for neuroprotection in very early cases of Parkinson’s (Ev-NIRT). 14 participants, taking place at University Hospital, Grenoble (France – click here to read more about this trial and click here to read more about the preclinical data).
  • New clinical trial registered exploring the effects of lithium on blood-based therapeutic targets in Parkinson’s. Phase 1 trial, 3 lithium doses for 6 months, 20 participants, assessing the benefits from lithium therapy (Click here to read more about this).
  • The “Study in Parkinson’s Disease of Exercise” (SPARX3) – a Phase 3 study of endurance treadmill exercise on changes in MDS-UPDRS; 12 months; 370 early stage PD randomised to 2 groups: 60% or 80% HRmax (30 mins, 4x per week – click here to read more about this).

 

Clinical trial news

  • The protocol of the INfusion VErsus STimulation (INVEST) study has been published. This is a randomized open label multicentre trial comparing continuous intrajejunal levodopa infusion with deep brain stimulation in Parkinson’s (NCT02480803 – to read more about this).
  • Alkahest initiates a Phase 2 Clinical Trial of AKST4290 in Parkinson’s with funding from the Michael J Fox Foundation. AKST4290 is an inhibitor against CCR3, the natural receptor for eotaxin. The 12 week “TEAL” study will involve 120 participants ( to read more about this).

  • IRLAB has decided to use the name mesopedam for its drug candidate IRL790, which is a novel potential treatment of L-dopa induced dyskinesias or psychosis in Parkinson’s ( to read more about this).
  • The team leading the Kyoto IPS-cell derived transplantation trial for Parkinson’s have provided a brief update. The team says none of the three transplanted patients have developed side effects (>12 months post surgery). 4 more transplants this year ( to read more about this).
  • As part of a merger agreement, we have learnt that Kainos Medicine Inc is planning to conduct a Phase 2 study in the US in Parkinson’s (& explore a new indication to treat multiple system atrophy MSA) with their FAS-associated factor 1 inhibitor, KM-819 ( to read more about this).
  • resTORbio announces interim results from 3 cohorts for Phase 1b/2a trial of the TORC1 inhibitor RTB101 in Parkinson’s. RTB101 is well tolerated, crosses the blood brain barrier, & reaches concentrations in CSF observed in preclinical models to inhibit activity of TORC1 ( to read more about this).

  • Bladder dysfunction affects up to 70% of people with Parkinson’s. The protocol for a multicentred randomised controlled trial for urinary problems associated with PD – the STARTUP study (Stimulation of the tibial nerve) – has been published ( to read more about this).

 

Other news

  • The EU announces funding of a €3m project to develop nanodevices against epilepsy & Parkinson’s. The IN-FET project (“Ion Neuromodulation for Epilepsy Treatment”) aims to develop new nanodevices to implant & modulate electrical activity of the brain ( to read more about this).
  • Manolo Bellotto (CEO of Gain Therapeutics) spoke at the BIO CEO 2020 conference in New York about new developments in his company, which is developing therapies for Parkinson’s (with support from the Michael J Fox Foundation & Silverstein Foundation)
  • Olaris has been awarded a grant from the Michael J Fox Foundation to “uncover the metabolic fingerprint of Parkinson’s patients” using nuclear magnetic resonance spectroscopy & AI algorithms ( to read more about this).
  • Researchers provide an interesting view point on long-term unsupervised mobility assessment in movement disorders like Parkinson’s. “Studies that directly compared assessments made in unsupervised & supervised… settings point to large disparities, even in the same parameters of mobility. These differences appear to be affected by psychological, physiological, cognitive, environmental, & technical factors” ( to read more about this).
  • Servier & Oncodesign announce that they have reached the first milestone in their collaboration on research & development into new LRRK2 kinase inhibitor candidates for Parkinson’s ( to read more about this).

  • Annovis Bio has been issued a patent for a method of treating Parkinson’s & other Lewy body conditions in humans for its lead compound, ANVS401 (posiphen). The drug is being testing in Alzheimer’s, but Annovis is planning a 50-patient Phase 2a study in PD ( to read more about this).
  • The Michael J Fox foundation & 23andMe researchers present the background to “Fox Insights” – a rich data set facilitating discovery, validation, & reproducibility in Parkinson’s research. Also discuss ‘Fox Den’ where qualified researchers can explore the data ( to read more about this and click here to read a summary).

  • The Michael J Fox foundation have also relaunched a redesigned version of the Fox Trial Finder website ( to see the new website and click here to read more about this).
  • Pharma company Biogen announced late Thursday that it would license two preclinical drugs from Sangamo Therapeutics both of which use genome-editing zinc fingers to regulate expression of genes involved in neurodeg. conditions like Alzheimer’s & Parkinson’s. The deal involves preclinical candidate ST-502, which targets alpha synuclein, & is being oriented towards conditions like Parkinson’s. As part of the deal Biogen also has exclusive rights to nominate up to 9 additional, undisclosed disease targets over the next 5 years ( to read more about this).

  • Ping pong for Parkinson’s! (Small study, unpublished results – to read a press release).
  • If you are interested in the Ambroxol in Parkinson’s clinical trial results & would like to learn more about what is happening next with this Cure Parkinson’s Trust & Van Andel Institute supported clinical development program, you should register & come along (Click here to read more about this).

 

Review articles/videos

  • Interesting discussion of Ferroptosis: past, present & future; Parkinson’s gets a mention ( to read more about this).
  • Bradykinesia is one of the cardinal motor symptoms of Parkinson’s disease, but its mechanisms are not fully understood. This review explores recent findings on bradykinesia pathophysiology, including the role of network dysfunction ( to read more about this).
  • Researchers provide an excellent mini review of the neuroanatomical features of the pedunculopontine nucleus, its susceptibility to Parkinson’s-related insults, & outline a role for PPN neurons in motor & sleep deficits in PD ( to read more about this).
  • “Tears – more to them than meets the eye” (cute title), reviewing recent data on the identification of potential tear-based biomarkers for Parkinson’s ( to read more about this).

  • Researchers provide us with a useful update on advances in elucidating the function of leucine-rich repeat protein kinase-2 (LRRK2) in normal cells & in Parkinson’s ( to read more about this).
  • “Diagnosis and Treatment of Parkinson’s Disease – A Review” (Click here to read more about this).
  • Glial cell line-derived neurotrophic factor (GDNF) is a topic of major interest to the Parkinson’s community. This short review looks are GDNF upregulation in glial cells during neurodegeneration & repair ( to read more about this).
  • Researchers offer a useful commentary regarding research (including clinical trials) exploring the rejuvenation of blood & bone marrow to slow aging-associated cognitive decline & Alzheimer’s ( to read more about this).
  • Researchers provide a review exploring whether mitochondrial dynamic dysfunction could be a triggering factor for inflammation associated chronic non-communicable conditions (such as Parkinson’s? – to read more about this).

  • “Parkinson’s disease, aging & adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair” ( to read more about this).
  • A useful review of mitochondrial E3 Ubiquitin Ligase PARKIN: Relationships with other causal proteins in familial Parkinson’s & its substrate-involved mouse models ( to read more about this).
  • Resarchers provide an overview on cerebrospinal fluid biomarkers in Parkinson’s, discussing their association with different molecular pathways involved either in pathophysiology or progression ( to read more about this).
  • “The issues above are well known in the scientific community, yet there is a critical lack of urgency to do anything about them because the system keeps churning” – a great blog by Parkinson’s advocate Ben Stecher (Click here to read more about this).
  • Researchers explore current challenges & future perspectives in the autophagy research in Parkinson’s ( to read more about this).

  • A review of the last 15 years (!!!) since the discovery of associations between LRRK2 & Parkinson’s ( to read more about this).
  • A summary of the topics discussed at the Krembil Research Institute Knowledge Gaps in Parkinson’s Symposium which was held in Toronto last April has been published. The meeting addressed many of the unanswered and outstanding issues in the field ( to read more about this).
  • Researchers discuss the evidence suggesting that the new contacts established between host & graft neurons may indeed be cell‐type specific, & how transsynaptic tracing can be used in the future to further elucidate the mechanisms of graft‐mediated recovery ( to read more about this).
  • Retrotope researchers provides an interesting review of the data supporting the use of polyunsaturated fatty acid deuteration (PUFA) against neurodegenerative conditions like Parkinson’s ( to read more about this).

  • Researchers discuss management of neuroinflammatory responses to AAV-mediated gene therapies for neurodegenerative conditions, including choice of AAV capsid serotypes, modifications to the vector/transgene, & immunosuppressive strategies ( to read more about this).
  • Researchers provide a timely discussion of the barriers to drug development for neurodegenerative conditions, & the opportunities that digital biomarkers may offer. Required reading ( to read more about this).
  • Researchers provides a review of evidence for the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the recent findings on its involvement in Parkinson’s ( to read more about this).

 

* * * * * * * * * * * *

And there it is, just some of the highlights from February 2020 – another very busy month of Parkinson’s research. Hopefully there will be bits and pieces of interest for everyone in the list. Much of the material used here was collected from the Science of Parkinson’s Twitter feed (and there is a lot more posted there each day).

Any thoughts/feedback would be greatly appreciated (either in the comments below, or contact me directly).

And now: on to March!!!

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EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.

In addition, many of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. None of the companies have requested that this material be produced, nor has the author had any contact with any of the companies or associated parties. This post has been produced for educational purposes only.

Published by Simon

I am the Director of Research at Cure Parkinson's. Before that I was working as a Parkinson's research scientist at the University of Cambridge where I conducted both clinical- and lab-based research on Parkinson's. I have worked in the Parkinson's research field for over 15 years - both academically and in biotech ventures. All of my views/opinions expressed here are solely my own, and may not reflect the views of my employer or associated parties.

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