Monthly Research Review – May 2020

 

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 May 2020.

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

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials (Oooh, new section for 2019!)
  • Clinical trial news
  • Other news
  • Review articles/videos

 


So, what happened during May 2020?

In world news:

May 11th – In two studies published in Nature, and Nature Ecology and Evolution, scientists describe hominin remains and artefacts excavated from the Bacho Kiro Cave (in Bulgaria) that indicate early humans were present in Europe around 46,000 years ago – suggesting the species shared the continent with Neanderthals for longer than previously thought.

May 18th – A Maryland restaurant preparing to reopen amid the ongoing COVID-19 pandemic unveiled its fleet of wheeled bumper tables designed to enforce social distancing:

 

May 27th – South Korean schools reopened as the country began easing COVID-19-associated lockdown restrictions.

May 29th – South Korea re-closed 200 schools as new cases of COVID-19 spike to 79, the highest daily figure in two months.

May 30th – The age of commercial human spaceflight officially began

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

In May 2020, there were 782 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (4565 for 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 6 pieces of Parkinson’s news

1. Skin in the game

News of a case study involving a personalized cell transplantation operation were published. The researchers collected skin cells from a gentleman with Parkinson’s, coverted them into stem cell, that they further differentiated into dopamine neurons. They tested these cells in a humanized mouse model, before growing more cells and bilaterally implanting them into the gentleman in question “without the need for immunosuppression”. Brain imaging (PET) indicates that the grafted cells have survived and the clinical data suggests improvement – though a placebo response may be at play ( to read more about this, click here to read the STATnews article about it – click here for the follow up article questioning the ethics of the study – and click here to read a SoPD post on this topic).

2. Getting a GRP on dyskinesia

Researchers reported that a protein called RasGRP1 as a critical factor in the development of levodopa–induced dyskinesia in Parkinson’s. They reported that it is rapidly up-regulated in the striatum of mouse & macaque models of PD; mice with no RasGRP1 had diminished levels of dyskinesia and importantly this did not affect the therapeutic benefits of levodopa. A novel target for treating dyskinesias? ( to read more about this, and click here to read a SoPD post on this topic).

3. PDCORE

Researchers involved in the Phase 2 GDNF trial proposed the “Parkinson’s Disease Comprehensive Response” (PDCORE) – a novel weighted composite endpoint integrating changes measured in 3 established outcomes. “Results are not described to provide post-hoc evidence of the efficacy of GDNF but rather are presented to further the debate of how current regulatory approved rating scales may be combined to address some of the recognized limitations of using individual scales in isolation” ( to read more about this and click here to read a SoPD post on this topic).

4. Gut to brain and back (but no vagus!)

French researchers reported that patient-derived alpha synuclein aggregates are able to induce nigrostriatal lesions & enteric nervous system pathology after either enteric or striatal injection in a non-human primate model, BUT α-synuclein pathological lesions were not found in the vagal nerve, which is believed to be a main conduit. “This study does not support the hypothesis of a transmission of α-syn pathology through the vagus nerve & the dorsal motor nucleus of the vagus”. Instead, the researchers suspect a possible systemic mechanism (Click here to read more about this).

5. Accessing the brain

Denali Therapeutics published back-to-back papers highlighting the development of blood brain barrier transport vehicles (TV) comprising an engineered Fc fragment, resulting in substantially improved CNS uptake & sustained pharmacodynamic responses (Click here and here to read the reports, and click here to read the associated press release/summary).

6. New tool for Parkinson’s research

Researchers have a bioRxiv manuscript presenting a novel high-throughput & hypothesis-free approach to detect the existence of Parkinson’s genetic risk linked to any particular biological pathway. Utilising polygenic risk scores, gene-set burden analyses, cell type expression specificity enrichment, & summary-data based MR, they “highlight several promising pathways & genes for functional prioritization & provide a cellular context in which such work should be done”. As part of this study, they also created a foundational resource for the Parkinson’s community that can also be applied to other neurodegenerative diseases with complex genetic etiologies: ( to read more about this).

 

Basic biology news

  • Researchers have a bioRxiv manuscript describing a human single-nuclei transcriptomic atlas for the substantia nigra (~ 17,000 nuclei), identifing a cell type association between Parkinson’s risk & oligodendrocytes ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated α-synuclein facilitates clathrin assembly in synaptic vesicle endocytosis ( to read more about this)
  • Researchers report that polymorphic α-synuclein strains – modified by dopamine & docosahexaenoic acid – interact differentially with Tau protein (in vitro – to read more about this).

  • Researchers present a fusion peptide containing an α-syn-binding domain & a short strong proteasome-targeting motif, which effectively induces α-syn degradation through proteasome pathway & protects cells from α-syn-induced mitochondria dysfunction ( to read more about this).
  • Researchers have a bioRxiv manuscript of the results from a screening study exploring a library of α-synuclein point mutants in yeast cells treated with small molecules related to α-syn pathobiology. This study was part of a graduate student course ( to read more about this).
  • Researchers have a bioRxiv manuscript exploring Parkinson’s-associated alpha-synuclein oligomerization & inclusion formation using bimolecular fluorescence complementation assays ( to read more about this).
  • Researchers have a bioRxiv manuscript highlighting how the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior in Parkinson’s ( to read more about this).
  • Researchers reports that thiamet‐G, a highly selective pharmacological agent that inhibits the glycoside hydrolase O‐GlcNAcase, blunts the cellular uptake of α‐synuclein fibrils. OGT inhibitor 5SGlcNHex increases the level of uptake of α‐syn‐PFFs (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that LRRK2-positive immune cells in the brain represent CD68+ pro-inflammatory, monocyte-derived macrophages (distinct from microglia). Rod a-syn fibrils stimulate LRRK2 kinase activity. LRRK2 mutations lead to enhanced recruitment of classical monocytes in response to a-syn, & LRRK2 kinase inhibition blocks a-syn fibril induction of LRRK2 protein. Interferon-g strongly induces LRRK2 kinase activity in primary human macrophages ( to read more about this).

  • Researchers have a bioRxiv manuscript presenting a new transgenic mouse (expressing an aSyn-GFP fusion protein under the control of native Snca regulatory elements) to facilitate studies requiring in situ detection of endogenous a-syn. “Intracerebral injection of aSyn pre-formed fibrils into KI mice induced the formation of aSyn-GFP inclusions with a distribution pattern similar to that observed in wildtype mice, albeit with attenuated kinetics due to the GFP tag” ( to read more about this).
  • Researchers report Parkinson’s-associated LRRK2 interacts with the GARP complex & promotes retrograde transport to the trans-golgi network. Depletion of GARP = more neurodegeneration. “LRRK2 influences both retrograde & post-Golgi trafficking pathways in a manner dependent on its GTP binding & kinase activity. This action is exaggerated by mutations associated with Parkinson’s disease & can be blocked by kinase inhibitors” ( to read more about this).
  • Researchers report the basic helix-loop-helix transcription factor sterol regulatory element binding protein 1 (SREBP1) as a central player (both required & sufficient) in the neurogenesis of midbrain dopamine neurons ( to read more about this).
  • Researchers report that Parkinson’s-associated LRRK-G2019S variant alters the magnitude & direction of behavioral responses to stress (in mice – click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that intracerebroventricular administration of cerebral dopamine neurotrophic factor (CDNF) rescues motor neurons in 3 animal models of ALS (by targeting ER stress – to read more about this).
  • Researchers report a role for intra-mitochondrial protein homeostasis in Parkinson’s-associated alpha synuclein fibril elongation. Interference (via intra-mitochondrial proteases) aggravates aggregation (Click here to read more about this).

  • Researchers report inbred F344 & Lewis rats show divergent dyskinesia expression, offering a novel model for understanding genetic modulators. Could be “a powerful tool for investigating the role for ‘dyskinesia-resistance’ genes downstream of ‘dyskinesia-susceptibility’ genes in modulating LID expression”. There is “a need to reevaluate currently accepted genotype-to-phenotype relationships in the expression of LID”. Striatal Nurr1 may still represent a novel anti-dyskinesia target (Click here to read more about this).
  • ZNF746/PARIS upregulation causes oxidative stress-related FoxO1 & p53 activation leading to p21 induction & cellular senescence of myoblasts. Prev research points to PARIS being important target for Parkinson’s ( to read more about this).
  • More PARIS research: Scientists demonstrate that ZNF746/PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss under conditions of PARKIN or PINK1 deficiency (in flies – to read more about this).
  • Researchers report that GCase deficiency increases the spread of α-synuclein pathology (in vitro). Authors speculate on whether this contributes to the earlier age of onset & increased cognitive issues associated with GBA-associated Parkinson’s ( to read more about this).
  • X1INH, an improved next-generation affinity-optimized hydrazonic ligand, attenuates abnormal copper(i)/copper(ii)-α-Syn interactions & affects protein aggregation in a cellular model of synucleinopathy (like Parkinson’s – to read more about this).
  • (Unfortunately named gene) HOTAIR drives autophagy in midbrain dopaminergic neurons in the substantia nigra compacta in a mouse model of Parkinson’s ( to read more about this).
  • Researchers report that activation of cortical somatostatin interneurons (via optogenetics) may constitute a less invasive alternative than subthalamic stimulation (in rats) – implications for Parkinson’s? ( to read more about this).
  • New bioRxiv manuscript suggests the identification of select G-protein coupled receptors as regulators of the ER-mitochondria contact (by drug screening). Points towards a new mechanism of action for beta-adrenergic receptor agonists ( to read more about this).

  • Researchers have a bioRxiv suggesting that mouse CNS dopamine neurons are endowed with a distinctive developmental program that leads them to adopt a different mode of connectivity (compared to glutamatergic & GABAergic neurons – to read more about this).
  • NatB is a N-terminal acetyltransferase complex that acetylate N-terminals of proteins. Researchers have a bioRxiv maunscript suggesting NatB-specific elements responsible for Parkinson’s-associated alpha synuclein recognition & N-term. acetylation ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that drosophila phosphatidylinositol 4-kinase IIIβ homolog, “Four wheel drive”, promotes mitochondrial fission (downstream of Drp1). FWD overexpression suppresses Parkinson’s-associated Pink1/parkin phenotypes ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that nicotinamide restricts neural precursor proliferation to enhance catecholaminergic neuronal subtype differentiation from mouse embryonic stem cells ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that eIF2α kinase HRI potentiates the autophagic clearance of cytosolic protein aggregates when the ubiquitin-proteasome system is inhibited ( to read more about this).
  • Researchers report Parkinson’s-associated PINK1 deletion induces brown adipose tissue dysfunction via a new mitochondria-NLRP3 pathway. NRLP3 deletion in PINK1 KO mice reversed brown adipose tissue dysfunction (Click here to read more about this).
  • Researchers propose a novel, inexpensive, & sensitive method (the Z-scan technique) to investigate the early & late stages of Parkinson’s-associated α-synuclein aggregation ( to read more about this and click here to read the press release).
  • Researchers report using single cell gene expression analysis to reveal graft composition & differences between human stem cell- & fetal cell-derived grafts that correct model of Parkinson’s (Click here to read more about this).

  • Researchers have a bioRxiv manuscript comparing 4 commonly used protocols for the isolation of recombinant alpha synuclein (from E. coli). Acid precipitation & periplasmic lysis yielded the highest % of monomer ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that mice can handle not having a combined loss of Parkinson’s-associated LRRK2 & Rab29. Safe for therapeutics targeting in humans? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting Hsp70 directly blocks Parkinson’s-associated alpha synuclein oligomerization, via an as yet unidentified, non-canonical interaction site in the C-terminal domain ( to read more about this).
  • Researchers have a bioRxiv manuscript outlining an image analysis pipeline for the quantification of mitochondrial fragmentation in the context of a rotenone-based in-vitro Parkinson’s model ( to read more about this).
  • Researchers use the framework of chemical kinetics to investigate the dynamical properties of oligomeric species. They are overwhelmingly nonfibrillar & predominantly dissociate back to monomers rather than maturing to fibrillar species ( to read more about this).
  • Researchers report that the fibrillar form of α-synuclein-specific scFv antibodies inhibit Parkinson’s-associated α-synuclein induced aggregation & tox. Also recognize intracellular inclusions in human post-mortem brain tissue, but not controls ( to read more about this).
  • Researchers report that the N- & C-terminal regions of αB-crystallin & Hsp27 mediate inhibition of amyloid nucleation, fibril binding, & fibril disaggregation. Implications for Parkinson’s (Click here to read more about this).
  • Researchers reveal a role for astrocyte GLP-1R signaling in maintaining mitochondrial integrity, & lack of GLP-1R signaling mounts an adaptive stress response resulting in an improvement of systemic glucose homeostasis & memory ( to read more about this).

  • Researchers have a medRxiv manuscript suggesting that coding somatic single nucleotide variants in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies. They assessed 66 samples from multiple postmortem brain regions and matched-blood samples, derived from 42 individuals with the following conditions: 26 Parkinson’s, 12 control, 3 Multiple system atrophy (MSA) & 1 Incidental Lewy Body case ( to read more about this).
  • Researchers report inhibiting thrombin (using dabigatran) improves motor function & decreases oxidative stress in the LRRK2 transgenic fly model of Parkinson’s (via reduced iNOS & NOX4 – click here to read more about this).
  • Phosphoglycerate mutase 5 (PGAM5) is a mitochondrial protein that interacts with & stabilises Parkinson’s-associated PINK1. Now Chinese researchers report PGAM5 regulates senescence via several mechanisms ( to read more about this).
  • I love fly genetics just for the names: Researchers have a bioRxiv manuscript suggesting that “Split-ends” is modulating lipid droplet content in adult Drosophila glial cells & is protective in a Parkinson’s model (paraquat toxicity – to read more about this).
  • Researchers characterized these effects for 12 known prolyl oligopeptidase (PREP) inhibitors, & report their effect on Parkinson’s-associated alpha-synuclein aggregation & autophagy cannot be predicted by their inhibitory efficacy ( to read more about this).
  • Researchers have a bioRxiv manuscript investigating transcriptomics in frontal cortex tissues of SIV virus-infected primates. They highlight poly (ADP-ribose) polymerases (PARPs) in the SIV-associated neurodegenerative processes ( to read more about this).
  • Interesting – in addition to Parkinson’s-associated alpha‐synuclein, Tau also accumulates in Crohn’s disease gut ( to read more about this).

  • Researchers present microfluidic-controlled stem cell regionalization (MiSTR), deconstructing brain development to a single WNT gradient & obtaining key insights into a complex rostro-caudal neural organisation & programming – implications for efforts to grow dopamine neurons from stem cells for cell transplantation ( to read more about this).
  • New bioRxiv manuscript suggesting that Parkinson’s-associated GBA influences extracellular vesicles. In flies, GCase within EVs, may explain how GCase in one tissue (eg muscle) could reduce protein aggregation in a distant tissue (eg brain – to read more about this).
  • Researchers report gut microbiota-derived, brain-penetrating polyphenolic acids (3-HBA; 3,4-diHBA; & 3-HPPA) show ability to effectively modulate Parkinson’s-associated α-syn misfolding, oligomerization & toxicity (in vitro – to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that D3-receptor homolog DOP-2, mitochondrial calcium uniporter MCU-1, & Parkinson’s-associated PINK-1 are required for nicotine-mediated protection of dopamine neurons ( to read more about this).
  • Nurr1 is critical 4 the development & maintenance of dopamine neurons. Researchers report that prostaglandin E1 (PGE1) & its metabolite, PGA1 interact with the ligand-binding domain of Nurr1 & stimulate its transcriptional function ( to read more about this and click here to read the press summary).
  • More Nurr1 data – researchers have a bioRxiv manuscript in which they assess a panel of 12 reported Nurr1 ligands for their Nurr1-de-pendent & Nurr1-independent transcriptional effects. Amodiaquine & chloroquin directly bind Nurr1 LBD ( to read more about this).

 

Disease mechanism

  • Researchers report that the GTPase Rab27b regulates the release, autophagic clearance, & toxicity of Parkinson’s-associated alpha-synuclein. Rab27b protein levels increased in postmortem brain lysates from PD & DLB patients (vs controls – to read more about this).
  • Researchers report Parkinson’s-associated LRRK2 in human iPSC macrophages & microglia is not involved in initial phagocytic uptake of bioparticles, but is required for RAB8a & RAB10 recruitment to phagosomes ( to read more about this).
  • Mice with reduced synaptojanin1 (synj1) exhibit Parkinson’s-like pathologies (age-dependent motor issues, alpha-synuclein accumulation, impaired autophagy & dopamine terminal degeneration). Reducing SYNJ1 transcript found in a subset of sporadic PD brains (Click here to read more about this).
  • IRLAB Therapeutics researchers have published the preclinical pharmacology results for their candiate drug IRL790 – a novel dopamine transmission modulator for the treatment of motor & psychiatric complications in Parkinson’s ( to read more about this).

  • Researchers report data that “supports the view that microglial exosomes contribute to the progression of α-synuclein pathology & therefore, they may serve as a promising therapeutic target for Parkinson’s” (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting “new insights into early signs of neural network pathology significantly expanding upon the current knowledge relating to the G2019S Parkinson’s-associated mutation” ( to read more about this).
  • Researchers report a novel liposome-based brain-targeting drug delivery system allowing for IP administration of dopamine that corrected a mouse model of Parkinson’s. No elevation in dopamine detected in the heart or liver ( to read more about this).
  • Scientists report a alpha-lipoic acid-3-n-butylphthalide conjugate (called Dlx-23) that protected multiple models of Parkinson’s (better than alpha-lipoic acid alone). Dlx-23 reduced free radicals, increased glutathione, & reduced mitochondria damage (Click here to read more about this).
  • Researchers report that Parkinson’s-associated α‐syn fibrils induce c‐src activation in neurons (via FcγRIIb‐SHP‐1/‐2‐c‐src pathway) & enhances signals for the uptake of α‐syn into neurons. C‐src inhibitor, saracatinib, reduces α‐syn propagation ( to read more about this).
  • Researchers report CD11b mediates locus coeruleus noradrenergic neurodegeneration (via NLRP3 inflammation-dependent microglial proinflammatory activation) in a neurotoxin mouse model of Parkinson’s. Glybenclamide treatment rescues the phenotype ( to read more about this).
  • Researchers outline drug repositioning for psychiatric & neurological disorders through a network medicine approach – highlighting potential candidates for Parkinson’s, Alzheimer’s, Huntington’s, autism, etc. They propose Santhera Pharmaceutical‘s Omigapil for PD ( to read more about this).

  • Researchers have a bioRxiv manuscript suggesting that human Parkinson’s-patient IPS-derived dopaminergic neurons in vitro exhibit reduced NAD+ levels. Nicotinamide mononucleotide treatment restores NAD+ levels ( to read more about this).
  • Researchers report that in primates a small amount of singular α-syn aggregates from postmortem human Parkinson’s brain is as toxic as larger amyloid fibrils present in the Lewy Bodies (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that TOM20 expression prevents Parkinson’s -associated α-synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain ( to read more about this).
  • Further support for RAGE inhibition: Researchers report RAGE silencing ameliorates neuroinflammation (via inhibition of p38-NF-κB signaling) in a mouse MPTP model of Parkinson’s ( to read more about this).
  • Could neuron‐astrocyte transmitophagy be critical for preventing the release of damaged mitochondria to the extracellular medium and the neuro‐inflammatory activity which characterizes Parkinson’s? (Click here to read more about this).
  • Researchers report developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of Parkinson’s-associated α-synuclein (PFF) -induced toxicity & motor deficits ( to read more about this).

  • Researchers report that the absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s-associated mutation in the synaptojanin 1 gene (Synj1 aka PARK20 – to read more about this).
  • Research team reports that Clioquinol improves motor & non-motor deficits in MPTP-induced primate model of Parkinson’s (via AKT/mTOR pathway – to read more about this).
  • Diesel exhaust extract exposure induces behavioral deficits & neuronal toxicity in zebrafish (viaa disrupting autophagy), which was mitigated by co-treatment with nilotinib. Could diesel be an environmental modifier potentially contributing to Parkinson’s? (Click here to read more about this and click here to read the press release).
  • Researchers present data suggesting that propagation of pathological α-synuclein from the urogenital tract to the brain initiates multiple system atrophy-like syndrome (Click here to read more about this).
  • Researchers report Salidroside (a glucoside of tyrosol found in the plant Rhodiola rosea) rescues in vitro & in vivo models of Parkinson’s (via inhibiting NLRP3-dependent pyroptosis – to read more about this).
  • Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that reduces inflammation in astrocytes, increased in post-mortem Parkinson’s brain. Overexpression of GPNMB protects against neurodegeneration in a MPTP PD mice ( to read more about this).
  • Researchers report PGC-1α knockout mice experience dopamine deficits, motor impairment & mitochondrial dysfunction at 10-months of age; neurodegeneration of dopamine neurons occurs at 20 months (Click here to read more about this).
  • Dual glucagon-like peptide-1 (GLP-1) receptor & glucose dependent insulinotrophic polypeptide (GIP) receptor agonist DA-JC4 ameliorates motor dysfunctions & protects dopaminergic neurons in Parkinson’s model (via AKT/JNK signal pathway – click here to read more about this).
  • Researchers screened 320 compounds for their ability to ameliorate the mitochondrial phenotypes of iPS cells derived from patients with familial Parkinson’s (PINK & PARKIN), & identify 4 candidate drugs that rescued cell phenotypes & PD fly models ( to read more about this).

 

Clinical research

  • A new study showing that Parkinson’s patients who carry both LRRK2 and GBA variants have a milder phenotype in average, compared to those with GBA mutations alone or to sporadic disease (Click here to read more about this).
  • The ENIGMA-Parkinson’s Study team has a MedRxiv manuscript outlining some of the results from their international multi-centre analysis of brain structure across clinical stages of PD. A thinner cortex in 38 of 68 regions in PD (vs controls). 2,367 PD patients (& 1,183 controls) involved in the study. Results: “HY staging indicated that a thinner cortex initially presents in the occipital, parietal & temporal cortex, & extends towards caudally located brain regions with increased disease severity”. The authors propose novel imaging signatures that are specific to Parkinson’s severity stages. And they also highlight the importance of such multicenter collaborations ( to read more about this).
  • A 65-year follow-up of 30,000 male British doctors “demonstrates a causally protective effect of current smoking on the risk of Parkinson’s, which may provide insights into the etiology of PD” ( to read more about this).

  • New paper on importance of validating algorithms for wearables in patient’s (unsupervised) own home environment – as opposed to just closely supervised lab ( to read more about this).
  • Researchers performed full sequencing of Niemann-Pick type C associated gene NPC1 on samples from 2,657 Parkinson’s patients & 3,647 controls sourced from three cohorts, & found no rare NPC1 variants associated with PD (Click here to read more about this).
  • Researchers have a bioRxiv manuscript identifying “a novel, highly specific & sensitive platelet-associated miRNA-based bio-signature” for discriminating between dementia with Lewy bodies & Alzheimer’s ( to read more about this).
  • Researchers suggests that cerebrospinal fluid total- & oligomeric-α-syn & TNF-α best discriminate asymptomatic LRRK2 mutation carriers from both symptomatic Parkinson’s patients & healthy controls ( to read more about this).
  • New data supports the notion that the initiating site of neuronal degeneration & tau pathology in progressive supranuclear palsy (PSP) seems to be similar in clinical subtypes, but the dynamics & propagation patterns distinguish them. “While neuronal tau accumulation is central in the pathogenesis, astroglial, & oligodendroglial tau accumulation is important & may precede neuronal tau pathology in the striatum, cortical regions, globus pallidus, & cerebellar white matter (versus dentate nucleus)” ( to read more about this).
  • Researchers have a medRxiv manuscript analysing 3 longitudinal cohorts (Tracking Parkinson’s, Oxford Discovery, & PPMI). No single variants associated with motor progression, but the APOE ϵ4 allele drives progressive cognitive impairment ( to read more about this).

  • Researchers have a medRxiv manuscript using Mendelian randomization to evaluate lipid-lowering drug targets for Parkinson’s prevention. ApoA5 & ApoC3 modulators highlighted ( to read more about this).
  • Researchers report creation of a gene expression classifier for predicting Parkinson’s rate of progression. PD-Prediction algorithm comprises of ALDH1A1, LAMB2, UBE2K, SKP1A & age ( to read more about this).
  • Whole exome sequencing identified a new compound heterozygous PARKIN mutation (c.850G > C (p.G284R) along with exon 4 deletion) in a Chinese family with early-onset Parkinson’s ( to read more about this).
  • Researchers report that motor dysfunction is a component of the clinical prodrome seen in some patients who go on to develop Parkinson’s ( to read more about this).
  • Researchers have a bioRxiv manuscript reporting a robotics-based system enabling the induction of a hallucination under controlled experimental conditions & evaluate individuals with Parkinson’s ( to read more about this).
  • Researchers have a medRxiv manuscript suggesting that dopaminergic stimulants (Ritalin, Adderall, etc.) may protect against Parkinson’s (Click here to read more about this).
  • Researchers present an overview of the prevalence & distribution of LRRK2 variants in Japanese Parkinson’s cohorts (Click here to read more about this).
  • Researchers find (self-reported) antibiotic use not associated with risk of Parkinson’s in the Nurses’ Health Study ( to read more about this).

  • Researchers have an interesting report exploring whether microstructural integrity of the pedunculopontine nucleus predicts postural & gait symptoms in Parkinson’s. Data based on 147 PD (& 65 controls) in PPMI study ( to read more about this).
  • Researchers report longitudinal brain connectivity changes & clinical evolution in Parkinson’s. 4 yr study of 146 PD patients, who performed motor & non-motor evaluations + serial resting state functional MRI (Click here to read more about this).
  • The Parkinson’s Study Group/DATATOP Investigators report that in untreated early‐PD subjects, low CSF Vit B12 predicted greater worsening of UPDRS “walking” item, whereas CSF total homocysteine was not associated with progression of cognitive impairment ( to read more about this).
  • The “Treatment & Trials Working Group of the International RBD Study Group” have an interesting review of challenges & opportunities in clinical trials for REM sleep behavioural disorder (a prodrome for synucleinopathies like Parkinson’s – to read more about this).
  • Researchers outline the protocol for randomised clinical trial to evaluate the potential of robotic-based technologies in rehabilitation of older people with Parkinson’s (Click here to read more about this).
  • Researchers report no significant difference in cognition between Parkinson’s with & without freezing of gait when adjusting for covariates (particularly disease severity – to read more about this).
  • Researchers report optimization of neuromelanin contrast in the substantia nigra & locus coeruleus using a magnetization transfer contrast prepared 3D gradient recalled echo sequence (spot the frog) – omplications for Parkinson’s ( to read more about this).
  • Japanese reseearchers report that 1 hour of 5,000-lux bright light therapy during the evening hours (19:00–21:00) improves sleep in patients with Parkinson’s. Authors suggest it may be due to the restoration of circadian function ( to read more about this).

  • Researchers report cerebrospinal fluid & peripheral cytokine profiles in 35 Parkinson’s patients are not closely related. CSF α‐synuclein/amyloid β may reflect the risk of developing PD dementia ( to read more about this).
  • Researchers report a retrospective cohort study finds “increasing use of short-acting but not long-acting beta agonists during follow-up was inversely associated with the risk of a new diagnosis of Parkinson’s”. Following 300K individuals (3568 with Parkinson’s) over a median 60 months, they did not find a similar association with long-acting beta agonists, which “does not support the proposed causal relationship between the beta agonists group of drugs & PD risk” ( to read more about this).
  • Researchers report that benign or ‘private’ variants (unique to individuals or families) in the PARKIN gene are associated with late-onset Parkinson’s (Click here to read more about this).
  • New data suggests increased cerebrospinal fluid levels of neurofilament light protein are associated with cognitive decline and motor impairment in Parkinson’s. But this is not an early event & a marker of conversion to cognitive impairment beforehand (Click here to read more about this).
  • Researchers have a medRxiv manuscript analysing longitudinal data (7yrs) from 418 patients with Parkinson’s & 185 controls & suggesting various blood test & vital signs are different between the groups.”Heart rate, systolic blood pressure, white blood cell fractions, neutrophil counts, serum albumin, sodium & AST [aspartate aminotransferase] were different between Parkinson’s & controls. The causality or genetic correlations of these biomarkers to PD were not observed” ( to read more about this).
  • Researchers eport the combining computational methods & pharmacoepidemiology to identify corticosteroids & methylxanthines as classes of drugs that should be further explored as potential disease‐modifers for Parkinson’s ( to read more about this).
  • Research report increased alpha-synuclein tear fluid levels in individuals with Parkinson’s. A non-invasive biomarker for PD? ( to read more about this).

  • Researchers report 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 & dementia with Lewy bodies (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that motor & nonmotor features in Parkinson’s are associated with distinct large-scale networks. The basal ganglia & cerebellum are core regions in all the networks ( to read more about this).
  • Researchers have a medRxiv manuscript suggesting that higher-order aspects of gait control are reliant on the cortical cholinergic system – separate from disease-related dopaminergic deficits – which are not addressed by subthalamic deep brain stiulation ( to read more about this).
  • Researchers report that the methylation level of CpG5 of the 5’‐UTR DAT 1 gene is different between Parkinson’s patients vs controls, & may be associated with the stage of disease (Click here to read more about this).
  • Researchers report changes in stool samples of 666 elderly TREND study participants suggesting that several risk & prodromal markers of Parkinson’s are also associated with changes in gut microbiome composition ( to read more about this).
  • Researchers report higher urate levels are associated with increased risk of levodopa-induced dykinesia occurrence in males with Parkinson’s. In males, high urate group had a 5.7‐fold higher risk of developing dyskinesias than low urate group (Click here to read more about this).
  • Oligodendrocyte-derived exosomes in blood significantly lower in multiple system atrophy (MSA) patients (vs Parkinson’s & healthy control subjects). No difference in α-syn concentrations in exosomes betwn groups. SNARE dysfunction implicated (Click here to read more about this).
  • Researchers ask when does postural instability appear in monogenic parkinsonisms? They systematically reviewed PubMed 1996–2017 studies in SNCA, PRKN, PINK1, LRRK2, etc-related monogenic parkinsonisms, & provide differential timelines ( to read more about this).
  • Researchers report that in addition to the well-established striatal deficit, there is PPMI evidence for a major extrastriatal serotonergic (123I-FP-CIT) impairment, & potentially altered 5-HT transmission in early Parkinson’s ( to read more about this).

  • Researchers explore organochlorines blood concentrations in a Parkinson’s cohort, & report higher levels of DDE were detected among PD patients (in comparison to controls – click here to read more about this).
  • An interesting study, albeit small, showing that SNCA hypomethylation may be an early biomarker for Parkinson’s and REM sleep behavior disorder ( to read more about this).
  • Under represented communities in Parkinson’s – interesting review of the literature regarding Parkinson’s in African Americans ( to read more about this).
  • Underrepresented communities in Parkinson’s – researchers report genetic characterization of Parkinson’s in Ecuador & Colombia. They find 8 PARKIN & 3 PINK1 variants not previously reported in Latin Americans (Click here to read more about this).
  • Researchers report that young onset Parkinson’s is associated with the risk for impulse control disorders, but their longitudinal study (403 individuals, 185 developed ICDs) suggests polygenic risk score is NOT associated with impulse control disorders (Click here to read more about this).
  • Researchers report an explorative study finding that substantia nigra echogenicity is associated with serum ferritin, gender & iron-related genes in Parkinson’s. Of 221 participants, 122 (55.2%) = SN hyperechogenicity, & 99 (44.8%) = SN hypoechogenicity (Click here to read more about this).
  • Researchers have a medRxiv manuscript suggesting molecular imaging (with PET) can predict clinical progression in progressive supranuclear palsy (PSP – to read more about this).
  • Researchers report on an analysis of the costs of the 3 main forms of treatment for Parkinson’s (deep brain stimulation, duodenal levodopa infusion, & apomorphine infusion) through real-world data in the Basque Country in Spain ( to read more about this).
  • Researchers report heterozygous loss of function variants in Parkinson’s-associated LRRK2 reduce protein levels but are not strongly associated with specific disease state ( to read more about this).
  • Smartphone meets smartwatch meets smart insoles – researchers explore mhealth for remote monitoring & management of Parkinson’s: determinants of compliance & validation of a tremor evaluation method ( to read more about this).

  • Researchers examined advanced glycation end products (Carboxymethyllysine & Carboxyethyllysine), oxidative stress markers, & micronutrients in plasma of Parkinson’s & Alzheimer’s patients (+ controls). They identify interesting sex differences ( to read more about this).
  • EXosomes in PArkiNsons Disease (EXPAND) study researchers report biomarker profile of older adults with PD defined by higher IL-8, MIP-1β, phosphoethanolamine, & proline, + by lower concentrations of citrulline, IL9, & MIP-1α ( to read more about this).
  • Researchers report that morphological changes may occur in the subthalamic nucleus of people with Parkinson’s, which likely impact the function of the direct & indirect pathways of the basal ganglia & movement control ( to read more about this).
  • Researchers report a smartphone-based method from the recent “Parkinson’s Disease Digital Biomarker DREAM Challenge”, which uses deep learning to identify digital biomarkers for self-reported PD. A future for at-home screening of PD? ( to read more about this).
  • Researchers have developed a new metabolic network reconstruction approach using organ‐specific info from literature & omics data to generate 2 sex‐specific whole‐body metabolic (WBM) reconstructions. Virtual medicine anyone? ( to read more about this).
  • Researchers conducted a pilot study for symptom-tailored stimulation exploring a combination of unilateral subthalamic nucleus & contralateral globus pallidus interna deep brain stimulation for the treatment of Parkinson’s ( to read more about this).

 

New clinical trials

  • Interesting new clinical trial registered exploring the delivery of Cerezyme® (GCase replacement) in Parkinson’s dementia patients using MR-guided focused ultrasound induced opening of the blood-brain barrier (small feasibility pilot study – click here to read more about this).
  • New clinical trial registered: Alkahest Inc are initiating a 12 week Phase 2 efficacy & safety trial of AKST4290 (a CCR3 inhibitor; CCR3 is the receptor for eotaxin) in 120 subjects with Parkinson’s (Click here to read more about this).

  • New observational clinical study registered: Exploring/validating of 2 non-motor scales (the Neuropsychiatric Fluctuations Scale (NFS) & the Shame in PARKinson’s disease (SPARK) Scale) in 300 people with Parkinson’s; supported by the Michael J Fox Foundation (Click here to read more about this).
  • New clinical study registered: IIR REGISTRY for the collection of real world data on the safety & efficacy of Ambroxol for patients with Gaucher disease or GBA-associated Parkinson’s – seeking 300 participants (Click here to read more about this).

  • New clinical trial registered: Bukwang Pharma. is initiating a Phase 2 trial assessing JM 010, a combo of buspirone & zolmitriptan, in 188 participants with Parkinson’s & moderate to severe dyskinesias; 12 week study (Click here to read more about this).
  • New clinical trial registered: “TARGET-PwP” is looking for 700 people with Parkinson’s to assess the Personal KinetiGraph® (PKG®) watch ( to read more about this).
  • New clinical study registered: Researchers will be exploring the effect of an adrenergic receptor blocker (Terazosin) on cardiac & striatal transporter uptake in pre-motor & symptomatic Parkinson’s (Click here to read more about this).

  • New clinical trial registered: A pilot study investigating the short term effects (12 Weeks) of “Lactobacillus plantarum PS128” (PS128) – a psychobiotic – on 60 people with Parkinson’s in Taiwan (Click here to read more about this).
  • New clinical study registered: researchers are exploring if physiotherapy is effective for people with early Parkinson’s (the PEEP study). Seeking 40 participants (Click here to read more about this).
  • New clinical study registered: researchers are evaluating the frequency & severity of sleep abnormalities in 240 people with GBA- &/or LRRK2-associated Parkinson’s, using a novel “home polysomnographic monitoring test” (Click here to read more about this).
  • New clinical study registered exploring aerobic exercise & brain health in Parkinson’s. 70 participants, 24 weeks of supervised aerobic exercise or standard care, followed by a range of imaging, biomarkers & clinical measures (Click here to read more about this).

 

Clinical trial news

  • Small open‐label Phase 1 futility studies find that neither salsalate nor young plasma had a detectable effect on disease progression in Progressive Supranuclear Palsy (PSP), but useful exploration of historical clinical, fluid & imaging biomarkers (Click here to read more about this).
  • The Parkinson’s Study Group NILO-PD investigators have posted a medRxiv manuscript outlining the results of the Phase 2 clinical trial evaluating the c-Abl inhibitor nilotinib in 76 people with PD ( to read more about this).

  • The PD COMM Collaborative Group provide the protocol for a multicentre, randomised controlled trial to compare the clinical & cost-effectiveness of Lee Silverman Voice Treatment vs standard NHS Speech & Language Therapy for Parkinson’s (Click here to read more about this).
  • The results of a 12 week randomized, double-blind, placebo-controlled trial of the effect of melatonin supplementation on clinical & metabolic outcomes in 60 people with Parkinson’s suggests “favorable effects” across various measures (Click here to read more about this).
  • The results of a double-blind, randomised, sham-controlled study of subthalamic nucleus deep brain stimulation with a novel multiple independent constant current-controlled device in Parkinson’s (‘INTREPID’ study). 313 participants enrolled across 23 sites (Click here to read more about this)
  • Anavex Life Science as they begin clinical testing a second orally-administered small molecule targeting sigma-1 & M1 muscarinic receptors (ANAVEX®3-71 or AF710B) which is intended for neurodegenerative conditions, like Parkinson’s ( to read more about this).

Other news

  • Photopharmics seeking to start Phase III trial for their noninvasive specialized phototherapy Parkinson’s treatment device in August this year, following FDA breakthrough device designation ( to read more about this).
  • MeiraGTx announces that it has initiated the process for cGMP-grade AAV-GAD material & expects to file an Investigational New Drug application in late 2020 or early 2021. AAV-GAD gene therapy for Parkinson’s takes another step forward ( to read more about this).

  • Erisyon has been awarded a Michael J Fox Foundation grant to investigate single molecule protein sequencing for the detection & validation of biomarkers that may have the potential for early detection of Parkinson’s ( to read more about this).
  • “Thankfully, rodents don’t smoke” – letters to editors are great! A reader response to the “Use of β2-adrenoreceptor agonist & antagonist drugs and risk of Parkinson’s” paper last July. The beta agonist debate is heating up! Here is the letter to the editor, here is the response from the authors, and then the editors felt that they need to get involved (Click here to read their thoughts).
  • Accure Therapeutics, a Spanish biotech targeting central nervous system conditions such as multiple sclerosis & Parkinson’s, has launched with a Series A of €7.6M. Keep an eye out for Act-02 – an inhibitor of Prolyl oligopeptidase being targetted for PD ( to read more about this).

 

Review articles/videos

  • Ten unsolved questions about neuroinflammation in Parkinson’s, “with the goal of stimulating research in the field & accelerating the clinical development of neuroprotective therapies based on anti‐inflammatory strategies” (Click here to read more about this).
  • An interesting editorial regarding the investigation of lymphocyte populations in patients with Parkinson’s ( to read more about this).
  • Prof Simon Lewis discussing the PASADENA study announcement (Click here to see more of his great videos)

  • A review of “Mendelian neurodegenerative disease genes involved in autophagy” from the best in the business ( to read more about this).
  • A useful review of Resveratrol & its derivatives as potential treatments for Alzheimer’s & Parkinson’s ( to read more about this).
  • Researchers provide an interesting review of mitochondrial retrograde signalling in neurological conditions, including Parkinson’s ( to read more about this).
  • Researchers explore cell-to-cell transmission of Tau & α-synuclein in this review ( to read more about this).
  • A wonderful video presentation from Claire Bale (Parkinson’s UK) to the “Peninsula Parkinson’s Research Interest Group” (PenPRIG) group on the topic of “Why there isn’t a cure for Parkinson’s:

  • PenPRIG has also made this video of Dr Stephen Mullin available who was discussing how we are moving “From Genes To Therapy” in Parkinson’s & he uses the GBA/ambroxol story as a good example:

  • Researchers discuss the management of advanced therapies in Parkinson’s during times of humanitarian crisis (specifically the COVID‐19 experience). “Most of us were unprepared to deal with this condition given that in many health care systems, telemedicine has been only marginally available or only limited to email or telephone contacts”. “We should consider this crisis as an opportunity to change our approach & encourage our hospitals & health care systems to facilitate the remote management of chronic neurological patients” – amen! ( to read more about this).
  • A short, but pretty thorough review of GBA-associated Parkinson’s (including potential pathological mechanisms, the prodromal period, clinical features, biomarkers, & therapeutic routes being explored – to read more about this).
  • Researchers discuss triggers, pathophysiology, & management of visual hallucinations in Parkinson’s ( to read more about this).

  • Aerobic exercise & healthy nutrition as neuroprotective agents for brain health in patients with Parkinson’s: A critical review of the literature ( to read more about this).
  • Researchers provides a useful review of modeling Parkinson’s with alpha-synuclein protein – how each model has contributed to our understanding of PD pathology & the advantages/weakness of each of them ( to read more about this).
  • Researchers review the multiple-hit hypothesis in Parkinson’s, involving LRRK2 & inflammation ( to read more about this).
  • Interesting section on Parkinson’s in this review of TRAP1 – exploring a metabolic hub linking aging pathophysiology to mitochondrial S-nitrosylation ( to read more about this).
  • Researchers provide an interesting short review of the development of GLP-1R agonists & their potential therapeutic value in treating Parkinson’s ( to read more about this).
  • Researchers provide an update describing the clinical spectrum of features that can be seen in multiple system atrophy (MSA), including premotor & non-motor features & opportunities for early diagnosis/intervention ( to read more about this).

  • Researchers provide a useful review of Fractalkine (CX3CL1) signaling & neuroinflammation in Parkinson’s ( to read more about this).
  • A minireview on more than 20 Years of the discovery of PARK2 (PARKIN) – the genetics of Parkinson’s (Click here to read more about this).
  • And finally (I am slightly biased, but), if you are looking for some good bed time reading, The Cure Parkinson’s Trust 2020 Annual Review is now available – a detailed summary of our research work and fundraising activities over the last year ( to download it).

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

And there it is, just some of the highlights from May 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 June!!!

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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.

The author of this post is an employee of the Cure Parkinson’s Trust. The Trust has not asked for this post to be written, and there has been no effort to highlight the work of the Trust over others (perceptions of any bias should be directed to the author). This post has been written by the author solely for the purpose of sharing what the author considers interesting information.


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