Monthly Research Review – April 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 April 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 April 2020?

In world news:

April 2nd – Billionaire Amazon founder Jeff Bezos donated $100 million to Feeding America, a nonprofit that helps food banks feed families in need (Source).

April 6th – In March, billionaire Jack Ma donated 1.1 million COVID-19 testing kits, 6 million masks and 60,000 medical use protective suits/face shields to Africa. On this date, he sent a second shipment (including 500 ventilators – source).

 

April 7th – Billionaire founder of Twitter, Jack Dorsey, announced he was donating $1billion (28% of his net wealth) to help fund COVID-19 relief (source).

(For more on how billionaires are supporting the COVID-19 effort – click here)

 

April 20th – Oil prices reached a record low (falling into negative values) due to the ongoing coronavirus pandemic and the Russia–Saudi Arabia oil price war

April 30th – Captain Tom Moore – a war veteran who has raised over £32.79 million for the NHS by completing 100 laps (25m/27yd) of his garden in 10 days – celebrated his 100th birthday

 

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

In April 2020, there were 976 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3340 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. Isradine/STEADY-PD clinical trial results:

The Phase III isradipine/”STEADY-PD” clinical trial results were published. Conclusion: “Long-term treatment with immediate-release isradipine did not slow the clinical progression of early-stage Parkinson’s” ( to read more about this, to read a lay summary, and click here to read a SoPD post on this topic).

2. Reprogramming inside the brain:

In vivo induced dopamine neurons re-programming alleviates motor dysfunction in a mouse model of Parkinson’s. Made possible via glial CRISPR CasRx downregulation of a single RNA-binding protein: polypyrimidine tract-binding protein 1 (Ptbp1 – to read more about this and click here to read a SoPD post on this topic)

 

3. PASADENA immunotherapy clinical trial announcement:

Pharmaceutical company Roche & biotech firm Prothena have announced that the Phase 2 PASADENA alpha synuclein immunotherapy (prasinezumab) trial in Parkinson’s did not meet the primary objective, but showed signals of efficacy. Treatment was well tolerated & safe. These results are from Part 1 of the study (52 week, double-blind, randomised, 3-arm study that enrolled 316 participants with recently diagnosed Parkinson’s, who were allocated to placebo, high dose, or low dose. Part 2 (52 week extension) is ongoing. Key sentence in the announcement: “Signals were observed on multiple prespecified secondary & exploratory clinical endpoints” ( to read more about this, click here to read a SoPD post on this topic, and click here for an interview with the investigators from the Michael J Fox Foundation).

 

4. T cell reactivity in early Parkinson’s:

Researchers report “α-Synuclein-specific T cell reactivity is associated with preclinical & early Parkinson’s”. Analysis of independent cohorts reveals elevated α-syn-specific T cell responses prior to diagnosis & declines after ( to read more about this topic and click here to read a press release about the research).

 

5. Ferroptosis

Researchers report the Parkinson’s-associated alpha synuclein aggregation drives ferroptosis (a programmed cell death dependent on iron), highlighting a new mechanism by which lipid peroxidation causes cell death. Interesting to note 3 different ferroptosis inhibitors (deuterated PUFAs, iron chelator Deferoxamine, & ferrostatin-1) significantly reduced oligomer-induced cell death back to basal levels in human iPSC control cells & in SNCAx3 cells ( to read more about this).

 

6. Putting the Parkin back into Parkinson’s

Cellivery Therapeutics present further data on their cell-permeable Parkin protein (iCP-Parkin), that rescues neurons from accumulation of damaged mitochondria & pathological α-synuclein. Interesting study. The researchers report iCP-Parkin autoubiquitination and cytoprotective activities do not require PINK1; it also induces mitophagy & mitochondrial biogenesis, & demonstrates neuroprotection in toxin-induced & α-synuclein–induced models of PD ( to read more about this).

 

Basic biology news

  • Researchers demonstrate antagonistic regulation of Rab8A by Parkinson’s-associated PINK1 & LRRK2, “indicating a potential crosstalk between PINK1-regulated mitochondrial homeostasis & LRRK2 signalling” (in vitro – to read more about this).
  • Researchers report Parkinson’s-associated RAB39B is localized to the cortex, hippocampus & substantia nigra of mice throughout postnatal life in mice ( to read more about this).
  • TMEM175, a lysosomal gene associated with Parkinson’s. Researchers reveal the mechanisms of permeation, selectivity & gating, laying the groundwork for understanding the role of TMEM175 in lysosomal function (Click here to read more about this).
  • The Canadian LRRK2 in inflammation team (CLINT) report Parkinson’s-associated LRRK2 is important for programming the neuroinflammatory phenotype of microglia. Introduce WAVE2 as an important microglial factor potentially downstream of LRRK2 ( to read more about this).

  • A study utilising monobromobimane labelling of the N-terminal of Parkinson’s-associated alpha synuclein finds that intermediate aggregates appear & disappear through fibrillization process; oligomers are highly dynamic ( to read more about this).
  • Researchers have a bioRxiv manuscript presenting laser capture microdissection coupled (Smart-seq2 RNA seq) of mouse & human dopamine neurons to identify 33 differentially expressed SNc- or VTA-specific markers, highlighting ZCCHC12, CDH13 & SERPINE2 ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that obtusaquinone (& analogs) binds to cysteine residues with particular affinity to Keap1, resulting in ubiquitination & proteasomal degradation of Keap1, & downstream activation of Nrf2 ( to read more about this).
  • Researchers have a bioRxiv manuscript providing additional evidence suggesting that impaired vesicle endocytosis is a cellular target of excess α-synuclein & advances understanding of potential mechanisms underlying disease pathogenesis in synucleinopathies ( to read more about this).

  • Researchers report that Brain & muscle ARNT‐like 1 (BMAL1) may play an essential role in the survival of dopamine neurons & maintains normal function of the dopamine signaling pathway via regulating microglia‐mediated neuroinflammation in the brain ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated LRRK2 regulates ciliation probability upstream of Tau Tubulin kinase 2 ( to read more about this).
  • New paper reporting that levels of heat‐shock protein Hsp27 are important for modulating the glycation‐associated cellular pathologies in synucleinopathies ( to read more about this).
  • The TMEM175 family constitutes K+ channels that are important for autophagosome turnover & lysosomal pH regulation. They are associated with the early onset of Parkinson’s. Now researchers provide the X-ray structure of a closed bacterial TMEM175 channel (Click here to read more about this).
  • Researchers report quantitative proteomic profiling of the rodent substantia nigra during aging, highlighting key processes that converges upon GFAP. Also see increases in TH: implications 4 Parkinson’s? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting elevated intracellular levels of Poly (ADP-ribose) (PAR) promote the transition of Parkinson’s-associated α synuclein into higher molecular weight forms. Quantitative measurements of post-mortem PD brain samples reveal that PAR-pα-synuclein interactions are predominant in pathological states. Interactions between PAR & α-synuclein involve electrostatic forces between negatively charged PAR & the N-terminal region of αSyn. The authors ask if PAR could be a biomarker for PD? “Such a finding, holds wide implications for early prognosis & further presses on the need to develop robust PARP inhibitors that reduce PARP-1 activity without eliciting toxicity in cells” ( to read more about this).

  • Chronic 2x increase in endogenous GDNF levels (in 5 cohorts of mice) found increase in dopamine levels, improvement in motor learning, & no side-effects/cancer. Results support rationale for further development of endogenous GDNF-based treatments/mimetic ( to read more about this).
  • Nontoxic & biocompatible black phosphorus quantum dots appear to have an exceptional capacity to inhibit insulin aggregation & to disassemble formed mature fibrils, even at an ultralow concentration (100 ng/mL). Implications for Parkinson’s? ( to read more about this).
  • Researchers have a medRxiv manuscript presenting a small RNA sequencing study of brain tissues from 43 Parkinson’s cases (& 88 controls). They identified 421 miRNA editing sites with significantly different editing levels in prefrontal cortices of PD cases ( to read more about this).
  • Researchers report analysis of microglia & dopamine neurons in the mouse substantia nigra pars compacta & ventral tegmental area over time (to 24 months). No change after 9 months in dopamine neurons, but increased microglial support/surveillance (Click here to read more about this).

  • Researchers report data indicating impaired mitochondrial-endoplasmic reticulum interaction & mitophagy in Miro1-mutant neurons, which may result in altered mitochondrial movement & disrupted mitochondrial turnover ( to read more about this).
  • Researchers report reduced C9ORF72 appears to suppress repeat-mediated elevation in autophagy, which exacerbates cognitive deficits, hippocampal neuron loss, glial activation & accumulation of protein in mice (ALS/FTD –  to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that variations in Rab expression may contribute to differences in the rate of neurodegeneration recorded in different dopaminergic nuclei in fly models of Parkinson’s ( to read more about this).
  • A powerful addition for gene therapy approaches for neurological conditions like Parkinson’s – small latency-associated promoters from the herpesvirus pseudorabies virus offer better/longer transgene expression ( to read more about this).
  • Researchers reveal the molecular basis underlying the direct interaction between Parkinson’s-associated α-synuclein & Tau (Click here to read more about this).

  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated phosphorylation at Tyr39 rearranges α-synuclein amyloid fibril structure (revealed by cryo-EM), highlighting the potential importance of post-translational modifications ( to read more about this).
  • Researchers report that Parkinson’s-associated retromer subunit, VPS29, regulates synaptic transmission & is required for endolysosomal function in the aging brain. In flies, it is dispensable for embryogenesis but required in aging adults ( to read more about this).
  • Researchers used machine learning approach to predict novel molecules that would inhibit c-Abl while also having minimal liability against heart. Two novel Ponatinib analogs identified for preclinical testing in models of Parkinson’s ( to read more about this).
  • French researchers report a preclinical study suggesting that partial inhibition of c‐Abl & reduction of α‐synuclein phosphorylation (at tyrosine 39) may not be a relevant target for Multiple system atrophy (MSA – Click here to read more about this).
  • Researchers report that c-Abl activation by α-synucleinopathy, highlighting a novel pathological mechanism linking with c-Abl/p53 activation, mTOR/AMPK/ULK1, & autophagy. Further support for targetting c-Abl in Parkinson’s ( to read more about this).

  • Researchers present results suggest that α-synuclein might interfere with the p38γ pathway & play a role in the mechanisms of synaptic dysfunction in dementia with Lewy bodies /Parkinson’s. More so than p38α perhaps ( to read more about this).
  • Japanese researchers present drug screen results that idenitfied molecules to improve ganglioside accumulation & neural dysfunction in GM1 gangliosidosis models via autophagy activation ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that lysosomal dysfunction (via gene inactivations of lysosomal biogenesis or acidification factors) causes vitamin B12 deficiency, which in turn affects mitochondrial biogenesis & fission ( to read more about this).
  • Researchers report that Tollip (via an association with Parkinson’s-associated Parkin) is an essential coordinator to sort damaged mitochondrial‐derived cargo to the lysosomes. “Overall, these selective mitochondrial quality control pathways may represent a more physiologically relevant mechanism in Parkinson’s pathology compared with mitophagy, & thus, dissecting their distinct mechanisms may provide novel & effective therapeutic targets” ( to read more about this).
  • Researchers have a new bioRxiv manuscript presenting a novel USP30 inhibitor FT3967385 which recapitulates USP30 KO & sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation. “The benign effects of USP30 loss or inhibition, make it a target candidate that can be considered for long term therapy. The availability of specific tool compounds, such as described here, will enable pre-clinical assessment of this strategy” …for Parkinson’s? ( to read more about this).
  • Researchers report that amantadine exerts its antidyskinetic effects via striatal Kir2 K+ channel inhibition. It also enhances induction of long-term potentiation ( to read more about this).
  • Researchers have a bioRxiv manuscript presenting a new GMP-compliant protocol to derive long-term neuroepithelial stem cell progenitors (lt-NES), which are multipotent, bankable, & karyotypically stable ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that astrocytes & neurons in the mouse neocortex & thalamus share brain region-specific transcriptional signatures. Regional specificity maintained following astrocyte-to-neuron reprogramming ( to read more about this).

  • Researchers report intra-striatal administration of AAV2.retro leads to extensive retrograde transport in the primate brain. Important implications for disease modeling & therapeutic development for neurodegenerative conditions, like Parkinson’s ( to read more about this).
  • α-cyperone reported to attenuate H2O2-induced oxidative stress & cell death in SH-SY5Y cells (via activation of Nrf2 – to read more about this).
  • Notch inhibitor Bruceine D reported protect mouse Parkinson’s model (MPTP) via increased Nrf2 activation; suppressing oxidative stress & inflammatory response (Click here to read more about this).
  • Researchers investigate the presence of doubly‐phosphorylated α‐Synuclein at tyrosine 125 & serine 129 In idiopathic Lewy body diseases (Click here to read more about this).
  • Researchers assess the probiotics effects of Lactococcus lactis MG1363 & an engineered strain (constantly produced GLP-1) in models of Parkinson’s & Alzheimer’s. New approach for reducing neuroinflammation? ( to read more about this).

  • Researchers report TNF-α plays a pivotal role in toxin-upregulated astrocyte activation & proliferation, supporting their critical roles in in CNS pathogenesis. Do astrocytes perform classical innate immune functions in the CNS? ( to read more about this).
  • Researchers report that inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro & in vivo. “ULK1 thus represents a novel therapeutic target in traumatic & degenerative diseases of the CNS” (like Parkinson’s? – to read more about this).
  • Researchers report ischemic injury precipitates neuronal vulnerability in basal ganglia of PINK1-/- mice, possibly via impairment of mitochondrial metabolism & higher oxidative stress. Could vascular comorbidity be involved in Parkinson’s? (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated Parkin mediates anti-oxidant reactions (H2O2 reduction & glutathione regeneration), leading to a range of oxidative modifications in Parkin itself ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that protein synthesis is suppressed in sporadic & familial Parkinson’s by LRRK2. Translation is 40% reduced in PD patient (G2019S and sporadic) fibroblasts (unchanged in ALS cells). In a neurotoxin model of Parkinson’s they find that LRRK2 activity increases, which leads to repression of translation & dopaminergic neuron atrophy both of which are prevented by LRRK2 inhibition ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated LRRK2 generated phosphoRab10 dramatically redistributes Myosin Va-RILPL2 complexes, which may block their normal roles in ciliogenesis ( to read more about this).

  • Researchers have a bioRxiv manuscript suggesting that clathrin-mediated endo-cytosis (CME) is a LRRK2-mediated, Parkinson’s relevant pathway. CME genes found to be associated with PD across multiple cohorts ( 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).
  • The world according to GARP. Researchers report inhibition of sphingolipid synthesis improves outcomes & survival in GARP mutant wobbler mice (a model of motor neuron degeneration). They suggest that “inhibiting the accumulation of toxic sphingolipid species may provide a therapeutic avenue fortreating such neurodegenerative diseases” (like Parkinson’s – to read more about this).
  • Astrocytes can transfer mitochondria – researchers & collaborators report that human iPSC-derived astrocytes rescue rotenone-induced mitochondrial dysfunction & dopaminergic neurodegeneration in vitro by donating functional mitochondria ( 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 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 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 & oligodendrocyte gene expression ( to read more about this).
  • Klogene Therapeutics researchers report a method to specifically activate the Klotho promoter (using zinc finger proteins constructed from modular building blocks & from naturally engineered Egr1 transcription factor backbone – to read more about this).

Disease mechanism

  • Researchers present a silicon-based agent that generates hydrogen, providing renoprotective & neuroprotective effects in models of kidney disease & Parkinson’s ( to read more about this).
  • Researchers have a bioRxiv manuscript present a new synuclein-transgenic mouse model for early Parkinson’s, which may reveal molecular features of the preclinical condition ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that JN403, an alpha-7-nicotine-acetylcholine-receptor agonist, reduces alpha-synuclein induced inflammation in vitro microglia but fails to rescue Parkinson’s mouse model ( to read more about this).
  • Researchers report Tubastatin A – a potent & highly selective HDAC6 inhibitor – protects dopaminergic neurons from alpha-synuclein toxicity ( to read more about this).
  • Researchers report that striatal Nurr1 levels facilitates the dyskinetic state & exacerbates L-dopa-induced dyskinesia in rodent models of Parkinson’s (even LID-resistant Lewis rats!). They also provide post-mortem evidence of Nurr1 expression in striatal neurons of L-DOPA treated PD patients. A re-think required on nurr1 as a neuroprotective target for Parkinson’s? ( to read more about this).

  • Other researchers report pharmacological inhibition of HDAC6 by tubastatin A – a selective HDAC6 inhibitor – attenuates NLRP3 inflammatory response & protects dopamine neurons (possibly via Prx2 acetylation) in models of Parkinson’s ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting proper regulation of PERK-eIF2α signaling in dopamine neurons is required for normal cognitive & motor function; also highlights caution in sustained PERK inhibition ( to read more about this).
  • New research finds Astragaloside IV – an antioxidant derivative from a traditional Chinese herbal medicine – prevents dopamine neuron degeneration in model of Parkinson’s (via inhibition of astrocyte senescence through promoting mitophagy –  to read more about this).
  • Researchers report cell-based high-throughput screening experiment that identifies 2 two compounds that activate Parkinson’s-associated PINK1-Parkin signaling in human dopamine neurons in vitro, & improved mitochondrial functions of PINK1-KO flies ( to read more about this).

  • Researchers report long-term treatment with Fluvoxamine – a selective serotonin reuptake inhibitor – decreases nonmotor symptoms & improves dopamine depletion in a postnatal stress rodent model of Parkinson’s ( to read more about this).
  • Researchers report deficits in motor performance, neurotransmitters, & synaptic plasticity in elderly GPR37 KO mice. Modeling of Parkinson’s also exacerbates the phenotype ( to read more about this).
  • Researchers report histology & cell culture studies suggesting that astrocytes have the capacity to act as antigen-presenting cells in Parkinson’s. Again astrocytes as a therapeutic target 4 chronic inflammation ( to read more about this).
  • Further support for calpain inhibition in models of Parkinson’s – researchers report that calpain plays a role in T cell activation. CD4+ T cells are upregulated in MPTP mouse model, attenuated with calpain inhibition (Click here to read more about this).
  • Researchers report deficits in motor performance, neurotransmitters, & synaptic plasticity in elderly GPR37 KO mice. Modeling of Parkinson’s also exacerbates the phenotype ( to read more about this).

  • Researchers explore the translational feasibility of lumbar puncture for intrathecal AAV administration, & suggest that delivery into the cisterna magna may represent a more feasible alternative. Implications for Parkinson’s gene therapy trials? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that Parkinson’s-associated α-Syn pathology in the olfactory system impacts in vivo neural activity & provide initial insights into its network-level effects ( to read more about this).
  • New data supports the hypothesis that subthalamic nuclei neurons & their distinct projections are implicated in pain hypersensitivity in mouse model of Parkinson’s. Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity ( to read more about this).
  • Researchers report dopaminergic progenitors derived from epiblast stem cells function similarly to primary VM-derived progenitors when transplanted into a mouse model of Parkinson’s ( to read more about this).
  • Researchers screened Rab GTPases in Drosophila dopaminergic neurons (with/without LRRK2-G2019S) & conclude that Rab10 is a valid substrate of LRRK2 in vivo ( to read more about this).

  • Researchers summarize the prevalence of causal Parkinson’s genes/risk factors in 74 epidemiological & genomic studies. Then do a meta-analysis of 385 hiPSC-derived neuronal lines from 67 independent original research articles which suggest “converging molecular pathways underlying neurodegeneration in a range of familial & sporadic forms of PD”, iPSC-PD-derived neurons potentially aiding “future personalized drug screens in preclinical research” ( to read more about this).
  • Researchers report unilateral intranigral delivery of β-sitosterol β-D-glucoside (BSSG) triggers pathological α-synuclein spreading & bilateral nigrostriatal dopaminergic neurodegeneration in a rodent model for Parkinson’s ( to read more about this).
  • A Michael J Fox Foundation-led consortium of researchers report preclinical data investigating Parkinson’s targeted LRRK2 inhibitor–induced effects on lung tissue. Results suggests reversible changes in nonhuman primate lungs without measurable pulmonary deficits ( to read more about this and click here to read a good summary of this study).
  • Researchers have a bioRxiv manuscript suggesting a novel functional role for Parkinson’s-associated alpha synuclein in neuronal innate immunity by a mechanism that promotes interferon-stimulated gene expression ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that astrocytes harbouring familial Parkinson’s mutations in SNCA are dysfunctional. Could they have a contributory role in the disease mechanism & pathogenesis of PD? ( to read more about this).

  • Researchers report a novel mechanism of how nitric oxide (via S-nitrosylation of GRK6 & CK2α) can enhance the phosphorylation of pSer129 α-synuclein in a mouse model of Parkinson’s ( to read more about this).
  • Alpha synuclein fibrils amplified from Parkinson’s, DLB and MSA postmortem brains behave differently in cultured neurons and when injected into rodent brains. More support for the concept of synuclein “strains”? ( to read more about this).

 

Clinical research

  • Researchers have a bioRxiv mauscript suggesting that different indices of glycemic control & body fat distribution on the Parkinson’s symptomatology deserves further investigation. “Our results showed that Parkinson’s patients are glucose tolerant with protection against T2D. Furthermore, central obesity may be protective against PD development, independent of glucose levels” ( to read more about this).
  • Researchers report that Parkinson’s-associated α-synuclein acts (via PI4,5P2) to elongate the main axon & collaterals, resulting in a higher density of axons in the striatal white matter tracts. New role for α-Syn in compensating mechanisms? ( to read more about this).
  • Using Harvard Biomarkers Study data – a longitudinal study accelerating discovery/validation of diagnostic & progression markers of early-stage Parkinson’s – researchers report on the robustness of caffeine intake & urate as factors inversely associated PD ( to read more about this).

  • Post‐traumatic stress disorder & traumatic brain injury are independently associated with increased relative Parkinson’s risk in a nationwide cohort of military service veterans. Suggests modest synergistic excess risk. Longitudinal confirmation required ( to read more about this).
  • Small study, but researchers provide clinicopathologic & genetic features of Multiple System Atrophy (MSA) with Lewy Body Disease ( to read more about this).
  • Researchers report increased α-synuclein levels in serum of Parkinson’s cases without known mutations (systemic deregulation of α-synuclein homeostasis?). Levels are negatively correlated with UPDRS part III score in A53T-PD cases ( to read more about this).
  • Olfaction involves 2 components: orthonasal (perception of smell molecules) & retronasal (sensory modality that produces flavour). New research indicates that orthonasal, but not retronasal olfaction is specifically impaired in Parkinson’s ( to read more about this).

  • Researchers present data raising the possibility that GBA variants & the G/G SNCA rs356219 polymorphism act synergistically to accelerate pathology & clinical progression in Parkinson’s ( to read more about this).
  • The prodromal dementia with Lewy bodies diagnostic study group propose operationalised diagnostic criteria for probable & possible mild cognitive impairment with Lewy bodies, intended for use in research settings (pending validation for use in clinic – to read more about this).
  • “Diagnosing REM sleep behavior disorder in Parkinson’s without a gold standard: a latent-class model study” ( to read more about this).
  • Researchers involved in the Michael J Fox Foundation Fox Insight Study explore digital marketing techniques that may allow researchers to increase, accelerate, & diversify recruitment for Parkinson’s clinical studies ( to read more about this).

  • Vitamin B12 levels are significantly lower at time of diagnosis in patients with Parkinson’s vs patients with Progressive Supranuclear Palsy (PSP), Frontotemporal Dementia (FTD) & Dementia with Lewy Bodies (DLB – to read more about this).
  • Researchers report the development & validation of the automated imaging differentiation in parkinsonism (AID-P) in a multicentre machine learning study (17 MRI centres across Austria, Germany & the USA –  to read more about this).
  • Further evidence that rare genetic variants in specific lysosomal genes are associated with Parkinson’s. Researchers investigated the association between PD & rare genetic variants in 23 lysosomal candidate genes in 4096 PD (vs equal controls). They report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, & VPS13C with Parkinson’s (Click here to read more about this).
  • Identification of circulating biomarkers that closely correlate with Parkinson’s has been difficult. A new pilot study provides a different vision of translational research in biomarker discovery by focusing on circulatory mitochondrial proteins ( to read more about this).
  • Researchers provide a ‘cautionary tale’ regarding a non-pharmacologic approach (mindfulness training) for the improvement of anxiety in Parkinson’s using mobile health technologies ( to read more about this).

  • Researchers analysed neuronal exosomes collected from 664 longitudinal serum samples & found 2-fold increase in α-syn in prodromal & clinical Parkinson’s (compared with controls & other neurodeg conditions – to read more about this).
  • Researchers report 2 single nucleotide polymorphisms in IL13 & IL13RA1 from individuals with idiopathic Parkinson’s that confer a gain-of-function that may increase the risk of developing PD ( to read more about this).
  • Researchers have a medRxiv manuscript suggesting differences in the presentation & progression of Parkinson’s based on sex. 40 clinical phenotypes, across 5,946 patients with a median follow-up of 3.1 years ( to read more about this).
  • More on sex differences: researchers report that males with Parkinson’s have significantly greater executive & processing speed impairments compared to females despite no differences in demographic variables (Click here to read more about this).
  • Further evidence of a connection between skin cancer & Parkinson’s – researchers use national health insurance claims records & find patients diagnosed with PD had a greater risk of skin cancer, especially male aged 65 years & above ( to read more about this).

  • Researchers report impaired motor recycling during action selection in Parkinson’s. Disrupted ability to perform this computation may result in motor slowing ( to read more about this).
  • Treating PD patients like athletes. Researchers highlight the importance of clinical exercise as a therapeutic intervention for Parkinson’s, particularly the benefits of applying sports science principles to PD management ( to read more about this).
  • Researchers explore the idea of expanding the search for genetic biomarkers of Parkinson’s into the LIVING brain. Transcriptomics on brain biopsies from PD & controls (Click here to read more about this).
  • The BELNEU consortium report that recessive loss of function mutations in ATP10B increase risk for Parkinson’s by disturbed lysosomal export of glucosylceramide & phosphatidylcholine. Interesting that both ATP10B & GBA1 reduce lysosomal glucosylceramide ( to read more about this and click here to read the press release).
  • Researchers involved with the Michael J Fox Foundation supported Parkinson’s Progression Markers Initiative (PPMI) study report that neuropsychiatric features can be common from the onset of PD, can increase over time, frequently comorbid, & fluctuate in severity ( to read more about this).

  • Researchers report on the design & the validation of a wearable mechatronic device for an at-home assessment of wrist stiffness in patients affected by Parkinson’s ( to read more about this).
  • Researchers explored the impact of immersive virtual reality technology (Oculus Rift 2) in Parkinson’s for use in upper limb rehabilitation. Intervention showed some positive results – & it sounds like a cool study to be involved in! ( to read more about this).
  • 101 Parkinson’s patients completed a questionaire on the ethical challenges of early PD detection. Majority are skeptical regarding early disclosure of risk, especially with regard to the lack of pharmacologic options (Click here to read more about this).
  • Researchers present results of a pilot study evaluating feasibility aspects of exploring exercise-induced neuroplasticity in Parkinson’s. Suggest further work on MRI setup, cognitive dual-tasks, & blinding procedure required ( to read more about this).
  • A new bioRxiv manuscript analyses post-mortem spinal cord tissue from sporadic cases of ALS and finds disrupted copper bioavailability, indicating that CuII(atsm) may be useful in sporadic cases of ALS, as well as those involving mutant SOD1 ( to read more about this).
  • Resarchers have a medRxiv manuscript suggesting NO support for a markedly higher Parkinson’s prevalence in the Lancaster Amish. Nor do they show non-motor symptoms occurring with prevalence different to the general US population ( to read more about this).

  • Interesting analysis of age at onset of Parkinson’s among Ashkenazi Jewish patients, evaluating the contribution of environment, LRRK2 p.G2019S, & GBA p.N370S variants. Results suggest that both genetic & environmental factors involved ( to read more about this).
  • Assessment of urinary dysfunction in 187 people with Parkinson’s finds that urinary symptoms & urodynamics were highly variable in PD patients, indicating that most patients may benefit from personalised management ( to read more about this).
  • Researchers report α-synuclein inclusions are abundant in non-neuronal cells in the anterior olfactory nucleus of the olfactory bulb in postmortem Parkinson’s brains. In 8% of microglia, but 0% of oligodendrocytes ( to read more about this).
  • Further evidence that visual hallucinations in Parkinson’s are not simply mediated by dopaminergic mechanisms ( to read more about this).
  • Researchers have a medRxiv manuscript presenting the utility of machine learning models to classify different movement disorders, like Parkinson’s, based on gait & balance characteristics from wearable motion sensors (Click here to read more about this).

  • The design of the “Walking and mobile Health (technology) to Increase Participation in Parkinson’s Disease” (WHIP-PD) study has been published. This is a phase II, 12 month, randomised controlled trial evaluating the effects of a cognitive-behavioral approach ( to read more about this).
  • Researchers describe the “RADboud indicators for PAlliative Care Needs in Parkinson’s Disease” (RADPAC-PD) tool – offering healthcare professionals support in initiating palliative care ( to read more about this).
  • Researchers have a bioRxiv manuscript proposing “a potential neuroimaging biomarker that accurately predicts progression, which may be useful as a clinical decision-making tool & in future trials of neuroprotective treatments” for Parkinson’s ( to read more about this).
  • Resarchers report data results indicating that differential gene expression signatures in Parkinson’s postmortem brain tissue are significantly confounded by underlying differences in cell type composition ( to read more about this).
  • Lower Vitamin B12 level at Multiple System Atrophy (MSA) diagnosis is associated with poorer prognosis. “Additional studies to explore this observation & assess the potential role of vitamin B12 as a modifiable survival factor are needed” (Click here to read more about this).

  • Researchers report PET imaging in non-manifesting carriers of Parkinson’s-associated LRRK2 G2019S mutation found reduced putaminal 18F-DOPA uptake in 5/8 individuals (3 had raised nigral 11C-PK11195 (microglial) binding – to read more about this).
  • Small study, but researchers present data indicating that the GLP1R rs3765467 GG genotype is a potential risk factor for Parkinson’s, especially for male & late-onset PD patients in the Chinese Han population (no association between rs6923761 & PD – click here to read more about this).
  • Further research indicating that serum neurofilament light chain levels could be a useful biomarker for Parkinson’s. Specifically, significantly increased in PD group (p = 0.010), & reflecting cortical neurodegeneration in de novo PD cases ( to read more about this).
  • Researchers report blood phosphorylated tau 181 levels predict tau & amyloid β pathologies, differentiate Alzheimer’s from other neurodegenerative conditions (eg Parkinson’s), & identify AD across clinical continuum (using data from 4 prospective cohorts – click here to read more about this).
  • Researchers present an unsupervised technique to generate objective measurements of movement quality in Parkinson’s during in-clinic & at-home activities. Unbiased symbolic movement representation captured with wrist worn sensors ( to read more about this).
  • Researchers report fractures occur more commonly during the prodromal period of Parkinson’s (vs controls), especially as diagnosis date approached, suggesting that people with PD may experience unrecognized motor & nonmotor symptoms (Click here to read more about this).

  • MIND‐MAPS consortium researchers report in vivo (imaging) evidence of mitochondrial, endoplasmic reticulum, & synaptic dysfunction in drug‐naive Parkinson’s patients (Click here to read more about this).
  • Researchers report that people with Parkinson’s show “a larger, but not better, motor adaptation ability than elderly individuals & young individuals, rather than a compatible or impaired ability”. Compensatory cerebellar functions? ( to read more about this).
  • Researchers report findings suggesting that breakdown of the blood brain barrier contributes to APOE4-associated cognitive decline independently of Alzheimer’s pathology, & might be a therapeutic target in APOE4 carriers ( to read more about this).
  • Researchers studied 447 participants involved in a clinical-autopsy cohort study to examine any associations of physical activity, postmortem brain pathologies, & parkinsonism. Higher physical activity was associated with less parkinsonism (Click here to read more about this).
  • Researchers report 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).
  • Researchers have a medRxiv manuscript suggesting that the 9-Hole Peg Test provides the most accurate tool for identification of the Parkinson’s stage & progression based on hand function impairment ( to read more about this).

 

New clinical trials

  • New clinical trial registered: The “Dopaminergic restauratIon by intraVEntriculaire Administration” (DIVE) study – evaluating direct delivery of a-dopamine in Parkinson’s (Click here to read more about this study and click here to read a SoPD post about this approach).
  • New clinical trial registered: Takeda Pharma is going to evaluate their muscarinic M1 receptor positive allosteric modulator, TAK-071, in people with Parkinson’s who have cognitive impairment & are at risk of falling (Click here to read more about this).
  • Inflazome have just registered a Phase 1 clinical trial in people with Parkinson’s for their NLRP3 inhibitor, inzomelid ( IZD174). It will be a short 4 week, 6 pariticipant PK/safety study ( to read more about this).

  • New clinical trial registered: the Education for Adapted Physical Activity in Parkinson’s Disease (ACTIPARK) study evaluating effectiveness of adapted physical activity education on Parkinson’s (Click here to read more about this).
  • New clinical trial registered: Kyowa Kirin are evaluating the effects of multiple therapeutic & supratherapeutic doses of KW-6356 (a selective antagonist of adenosine A2A receptors) in 128 healthy adults – this therapy is being developed for Parkinson’s (Click here to read more about this).

  • New clinical trial registered: Early Phase 1 study exploring the role of the noradrenergic system in the nonmotor symptoms of Parkinson’s (NAinPD), evaluating the use of Yohimbine (an alpha-2 adrenergic antagonist) in 22 people with PD (Click here to read more about this).
  • New clinical trial registered in China: Observational study (supported by the Michael J Fox Foundation) investigating LRRK2 activity & markers of Parkinson’s in G2385R Carriers. Recruiting 200 participants (with & w/o PD – click here to read more about this).
  • Inhibikase Therapeutics set to initiate Phase I clinical testing (SAD/MAD dosing) of their cAbl inhibitor IkT-148009 in 112 healthy individuals, with the goal of eventually testing in Parkinson’s (Click here to read more about this).

 

Clinical trial news

  • A randomised controlled clinical trial (n=72 PwPs) of telephone-based cognitive behavioral therapy for depression in Parkinson’s found it is an effective intervention for a significantly unmet PD treatment need, bypassing access barriers (Click here to read more about this).
  • Axovant reports that they have completed dosing of all participants in the second cohort of Phase 2 AXO-Lenti-PD dose escalation “SUNRISE-PD” gene therapy study for Parkinson’s ( to read more about this).

  • Results of a double-blind, randomized controlled trial of duloxetine for pain in Parkinson’s have been published. 10 weeks of duloxetine (40 mg/day) had no effect on pain, but exploratory analyses suggest improvement in UPDRS part III & PDQ-39 (vs placebo – click here to read more about this).
  • Tiny 8-week pilot study, but providing some evidence that a high-intensity exercise progressive-cycle program may help improve quality of life & motor symptoms in a Parkinson’s cohort ( to read more about this).

 

Other news

  • The International Parkinson Disease Genomics Consortium have a bioRxiv manuscript presenting present a GWAS locus browser application that combines data from multiple databases to aid in the prioritization of genes associated with Parkinson’s genome wide association studies (GWAS) loci. They highlight DYRK1A (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A; Locus 78, rs2248244) as a good candidate for more functional Parkinson’s studies ( to read more about this and to see the browser).

  • Designing a new model of care: PRIME-PD – “Proactive and Integrated Management and Empowerment in Parkinson’s Disease” ( to read more about this).
  • Interesting annual update from the Silverstein Foundation – remarkable progress made in just 3 years! Look forward to learning more about Vanqua Bio, Chamishi Therapeutics, & other GBA-associated Parkinson’s projects in coming months ( to read more about this).

  • Researchers report the proceedings of the 7th annual deep brain stimulation think tank meeting, held in September. Discussing advances in neurophysiology, adaptive DBS, virtual reality, neuroethics & technology ( to read more about this).
  • Sofinnova & Abbvie lead $38 million series A funding for Nitrome Biosciences. The funds will push Nitrome’s Parkinson’s program toward clinical proof-of-concept studies & aid R&D efforts for other indications ( to read more about this).

  • Research discuss how advances in telemedicine & remote monitoring for Parkinson’s will hopefully persist after the COVID-19 crisis has passed. “Telemedicine for chronic neurological disorders should become part of the new normal rather than the exception” (Click here to read more about this).

 

Review articles/videos

  • For those of your interested in watching some video Parkinson’s-related presentations of high level research being conducted by young scientists, have a look at the 3Pseminar series (Click here to read more and watch the videos). There is also a Facebook page where you can ask the presenters follow up questions ( to see that page). Here is an example of one of my favourite sessions:
  • Parkinson’s gets a mention in this mini review of “Glucose, glycolysis, & neurodegenerative diseases” (Click here to read more about this).
  • “The majority of PD-associated genetic variants are located in non-coding regions of the genome“. Researchers ask “Could non-coding genetic variation be the missing heritability link in Parkinson’s?” in this interesting review ( to read more about this).
  • Researchers & collaborators provide a very thorough systematic review investigating the use of technology to measure free-living symptom & activity outcomes in Parkinson’s in the home (or home-like environment – to read more about this).
  • Interesting discussion on β-hydroxybutyrate & its metabolic effects on age-associated pathology, with a section on Parkinson’s ( to read more about this).
  • Parkinson’s advocate Ben Stecher shared a video this month proposing basketball as a therapy for Parkinson’s:
  • A review of the emerging functions of Parkinson’s-associated LRRK2 & Rab GTPases in the endolysosomal system ( to read more about this).
  • A useful minireview exploring protein-protein interactions in the biogenesis of Parkinson’s-associated alpha-synuclein, highlighting novel potential therapeutic targets ( to read more about this).
  • Nuclear factor-κB (NF-κB) is a protein compex that regulates inflammation & apoptosis. It consist of 5 subunits (c-Rel, p65/RelA, p50, RelB, & p52). This new review explores interplay between NF-κB dysregulation & α-syn pathology in Parkinson’s ( to read more about this).
  • Interesting review of the possible biology underlying the links between traumatic brain injury & Parkinson’s ( to read more about this).
  • “Can precision medicine unlock the potential to halt the progression of Parkinson’s?” ( to read more about this).
  • Another excellent video from Parkinson’s advocate Dr Soania Mathur (Unshakeable MD) regarding COVID-19 and Parkinson’s. This video involves asking the experts:
  • Researchers review the “mechanisms of action of some of the major herbal products with potential in the treatment of neurodegenerative disease according to their molecular targets, as well as their regional sources (Asia, America & Africa)” ( to read more about this).
  • Interesting review of GLP-1 agonists and their potential as disease-modifying therapies for Parkinson’s ( to read more about this).
  • An update on the management of Parkinson’s for general neurologists ( to read more about this).
  • A useful review of proteostasis failure in neurodegenerative conditions like Parkinson’s, with a focus on oxidative stress ( to read more about this).
  • Interesting review on non-prion mechanisms & loss-of-function (rather than gain-of-functio toxicity of amyloids ( to read more about this).
  • Researchers provide a useful review of advantages & recent developments of autologous cell transplantation for Parkinson’s ( to read more about this).
  • Could type of skin fungus be involved with Parkinson’s in some way? The Malassezia Project offered this video to propose the idea:
  • Both Neuropore & Lysosomal Therapeutics got special mentions in this intersting summary of Parkinson’s therapy results that were presented at the ADPD meeting this month ( to read more about this).
  • Researchers provide a useful review of the noradrenergic system in Parkinson’s (including an interesting section on L-dopa – click here to read more about this).
  • Interested in targeting autophagy-related protein kinases for therapeutic purposes in conditions like Parkinson’s? This review could be a good place to start ( to read more about this).
  • A useful review of small heat shock proteins in neurodegenerative diseases (with a small section on Parkinson’s – to read more about this).
  • Do Lewy bodies contain alpha-synuclein fibrils? Does it matter? This review provides a brief history and critical analysis of recent reports ( to read more about this).
  • Researchers provide a review of the association between Type 2 diabetes mellitus & Parkinson’s (epidemiological links, plus potentially shared cellular mechanisms & relevance for disease modification efforts – to read more about this).

  • Parkinson’s & the immune system – a review of associations, mechanisms & therapeutics ( to read more about this).
  • Haven’t looked at this topic for a while, but keen to read about the new developments in brain-derived blood exosomes. A promising source of biomarkers for Parkinson’s? ( to read more about this).
  • An interesting article on stem cells in the clinic and how are they regulated (Click here to read more about this).
  • Researchers provide a useful review of Lymphocyte-Activation Gene 3 (LAG3) protein as a possible therapeutic target for Parkinson’s. Exploring the molecular mechanisms connecting neuroinflammation to α-synuclein spreading pathology ( to read more about this).
  • Finally, I recommend readers listen to this interview by Larry Gifford of the living legend Dave Clark. It is an honest & frank discussion about living with Parkinson’s. Postivity, clarity & some hard stuff. Clinicians/researchers – take a moment out of your day & listen (Click here to listen).

 

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

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

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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.

3 thoughts on “Monthly Research Review – April 2020”

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