Monthly Research Review: March 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 March 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 March 2020?

In world news:

March 1-31st – Obviously, COVID-19.

 

March 9th – A research team at the Los Alamos National Laboratory (US) has developed a less expensive water electrolysis system, offering a more viable way to store energy from solar and wind power in the form of hydrogen fuel (Click here to read the study and click here to read the press summary).

March 10th – Researchers at the Dark Energy Survey (DES) study reported the discovery of more than 300 trans-Neptunian objects orbiting the Sun (all were 30-90 times the distance of Earth to the sun away – Pluto is 40x; click here to read the study and click here to read the press summary).

March 15th – Faced with national lockdown due to the current coronavirus/COVID-19 situation, Italians kept themselves occupied in wonderful ways:

 

March 16th – Of the 44 COVID-19 vaccines under development, one of the first went into clinical trial on this day. Biotech firm Moderna announced the dosing of the first participant in their NIH-led Phase 1 study of mRNA Vaccine (mRNA-1273) against SARS-CoV-2 (The trial ready vaccine was delivered to NIH in just 42 days from sequence selection!!! – Click here to read more about this). #Godspeed

March 26th – Daniel Matarazzo made the world smile with his Coronarvirus-parody of Supercalifragilisticexpialidocious. In case you missed it, enjoy:

 

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

In March 2020, there were 719 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2475 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 4 pieces of Parkinson’s news

1. Prosthetic limbs for neurons

Combining genetic engineering & polymer chemistry, researchers at Stanford University directly leveraged complex cellular architectures of living organisms to synthesize & assemble bioelectronic materials. Implications for Parkinson’s? ( to read more about this and click here to read the press release).

2. New life for Neurturin?

Analysis from the longest post-mortem trophic factor gene therapy Parkinson’s cases reported to date is really interesting! AAV2-neurturin (CERE120) did not meet primary endpoint in its clinical trial, but this data suggests biological effect. In the putamen, TH+ fibres were observed in areas of detectable neurturin expression; In the nigra, melanized neurons displayed intense TH & RET expression in the patient where CERE120 was directly delivered to the nigra; No difference in the degree of Lewy pathology. α-synuclein aggregates were detected in neurturin+ neurons; present post-mortem study involved 2 patients (8 & 10 years post-surgery); NRTN only covered relatively small areas of the putamen (3.75 & 12.40%, respectively). Does the poor spread justify another clinical trial? ( to read more about this, click here to read a lay summary, and click here to read a SoPD post about it).

3. Direct delivery of dopamine

French researchers demonstrated the feasibility of direct administration of a stable form of dopamine (“A-dopamine”) into the brain in a primate model of Parkinson’s (MPTP). They reported improved dopa-responsive motor and cognitive symptoms, and no dyskinesia under continuous A-dopamine delivery (vs peripheral L-dopa). A biotech company – called InBrain Pharma – has been set up to clinically develop this new approach ( to read more about this and click here to read a SoPD post on this topic).

4. Going viral

German researchers report disruption of cellular proteostasis (in human dopamine neurons & mouse brains) by H1N1 influenza A virus causes Parkinson’s-associated α-synuclein aggregation. H1N1 infection in human dopamine neurons in cell culture “leads to the formation of α-synuclein & Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but NOT of tau or TDP-43 aggregates, indicating a selective effect on proteostasis”. Oseltamivir phosphate prevented aggregation. “In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1” in mice ( to read more about this and click here to read a SoPD post on this topic).

And before we begin the rest of the post – special announcement:

Calling all PhD students and postdoctoral researchers!

Feeling isolated by social distancing?

Sick of your career being quarantined?

Looking for a means of sharing your research?

Or simply interested in watching some fascinating academic presentations focusing on Parkinson’s and related conditions while you are stuck at home?

Check out both 3Pseminars (being co-ordinated by the Van Andel Institute and The Cure Parkinson’s Trust) and also PD seminars (which is supported by Parkinsons’s UK). 3Pseminars will be held on Tuesdays and Thursdays (both at 5pm UK, 12pm EST), and PD seminars will be on Fridays (at 12pm UK).

 

Basic biology news

  • Researchers report expression of a single gene, Rap guanine nucleotide exchange factor 3 (Rapgef3), is strongly up-regulated in the absence of Parkinson’s-associated LRRK2 (including inhibition) & down-regulated in its presence. Analysis of a sub-clinical infection mouse model (S. typhimurium) indicated LRRK2 subtly modifies the inflammatory response. Elevated levels of Rapgef3 encoded EPAC-1 protein in activated macrophages lacking LRRK2. Results suggest a role for LRRK2 in murine immune cell chemotaxis ( to read more about this).
  • Researchers report the E193K variant modifies Parkinson’s-associated LRRK2-protein interactome & reduces its binding to synaptic vesicle. LRRK2-E193K expression increases the frequency & time length of synaptic vesicle fusion events ( to read more about this).
  • Aged (20yrs+) monkeys with spontaneous Type 2 diabetes develop Parkinson’s-associated alpha-synuclein accumulation, aggregation, & phosphorylation in the pancreatic islets & different brain regions (compared to the age-matched controls – to read more about this).

  • Researchers report astrocytic glycolysis controls cognitive functions in mice. Supplementation with L-serine in the diet prevents both synaptic & behavioural deficits in AD mice. They propse oral L-serine as a ready-to-use therapy for Alzheimers ( to read more about this).
  • The future of Parkinson’s deep brain stimulation? Researchers have a bioRxiv manuscript presenting injectable magnetoelectric nanoelectrodes that wirelessly transmit electrical signals to the brain in response to an external magnetic field ( to read more about this).
  • More miniaturization: researchers have an updated version of their bioRxiv manuscript proposing magnetoelectric materials for wireless power delivery enabling miniature bioelectronics for clinical & research applications ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting exifone is a potent activator of HDAC1 mediated deacetylation, providing a novel therapeutic angle for protecting genomic integrity in the context of neurodegeneration & aging ( to read more about this).
  • Researchers have a bioRxiv manuscript in which they conducted RNA-sequencing on 864 samples (12 brain regions) from 131 normal individuals & identified enrichment of neuropsychiatric disease risk variants in brain wide & multi-regional modules ( to read more about this).
  • Parkinson’s-associated DJ-1 reported to suppresses ferroptosis (via preserving the activity of S-adenosyl homocysteine hydrolase). Inhibition of DJ-1 potently enhances the sensitivity of cancer cells to ferroptosis inducers both in vitro & in vivo ( to read more about this).
  • Researchers compared 11 compounds, extracted from Chinese medicinal herbs & found that Salvianolic acid B & dihydromyricetin exhibited inhibition of Parkinson’s-associated α-syn aggregation, seeded fibril formation & toxicity in vitro ( to read more about this).

  • New interaction between 2 Parkinson’s-associated proteins: DJ-1 is required for S-nitrosylation of Parkin, which positively affects mitochondrial function. Could denitrosylation of Parkin (via DJ-1 inactivation) contribute to PD pathogenesis? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that GTPases Rab27b plays a role in the release, clearance, & toxicity of alpha synuclein, & may ultimately be involved the pathogenesis of synucleinopathies, like Parkinson’s ( to read more about this).
  • Researchers report that stimulation of L‐type calcium channels increases tyrosine hydroxylase & dopamine levels in ventral midbrain cells derived from human skin ( to read more about this).
  • Researchers report brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson’s (duplication SNCA gene) – dopamine neurons VS cortical projection neurons ( to read more about this).
  • Using bioinformatics, mutation & NMR, researchers have identified a short motif (7-residue sequence, named P1; residues 36–42) in the N-terminal region of Parkinson’s-associated α-synuclein that is critical for both aggregation & function ( to read more about this and click here to read the press release).
  • Further cryo-EM structure data of full-length α-synuclein amyloid fibril with Parkinson’s familial A53T mutation ( to read more about this).
  • Korean researchers report the salient features of monomeric alpha-synuclein (revealed by NMR spectroscopy – to read more about this).

  • Researchers have a bioRxiv manuscript suggesting that microfluidic free-flow electrophoresis is capable of separating heterogeneous oligomer mixtures on a timescale of seconds – faster than other conventional techniques ( to read more about this).
  • New data begs the question, could “differences in the clinical phenotypes of familial Parkinson’s disease… be associated with differences in the mechanism of formation & the structural characteristics of the aggregates” (Click here to read more about this).
  • Researchers provide a global view of the mitochondrial ubiquitylome dynamics in response to Parkinson’s-associated Parkin & PINK1 activation under endogenous protein levels in induced neurons ( to read more about this).
  • Researchers have a bioRxiv suggesting loss of DJ-1 function in fly & human cell models of Parkinson’s produces an enhancement of key glycolytic enzymes. Further boosting glycolysis with meclizine or dimethyl fumarate attenuates both models ( to read more about this).
  • Pharmacologically & genetically reducing the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) pathway reduces sleep in flies & zebrafish (increasing PERK increases sleep). PERK suppression is already being explored for Parkinson’s ( to read more about this and click here to read the press release).
  • Researchers report Parkinson’s-associated α-synuclein activates microglia, which in turn engulf α-synuclein for degradation (via selective autophagy – termed “synucleinphagy“). Requires microglial TLR4-NF-κB-p62 pathway ( to read more about this).
  • Mice deficient in GM1 manifest both motor & non-motor symptoms of Parkinson’s; successfully treated with synthetic form of GM1 ganglioside (Click here to read more about this).

  • Researchers have a  characterising the essential SNARE protein Ykt6, revealing a novel mechanism by which Ykt6 conformation & activity is regulated by Ca2+ signaling with implications in Parkinson’s ( to read more about this).
  • Researchers report that Crohn’s disease-associated LRRK2 mutations are significant modifiers of innate immune response in CD14+ monocytes, & Parkinson’s-associated LRRK2 mutation may contribute to reduced antigen presentation response. Study collected CD14+ monocytes from 46 people with CD, 51 control cases, 16 Parkinson’s cases, & 16 people with PD-linked LRRK2 mutation. Ex vivo IFN-γ stimulation enhanced TNFA, IL12, HLADRA1 & LRRK2 expression, suppressed by FK506 but enhanced by LRRK2 inhibitor GSK2578215A ( to read more about this).
  • Researchers report GTP‐binding inhibitors (68 and Fx2149) increase Parkinson’s-associated LRRK2‐linked ubiquitination & Lewy body‐like inclusions. Results suggest LRRK2 GTP‐binding activity is critical in ubiquitination & aggregation (Click here to read more about this).
  • Researchers report Mdm2 stimulates catalytic activity of Parkinson’s-associated parkin & promotes its biological functions in intact cells ( to read more about this).
  • Researchers report Epigallocatechin gallate (EGCG) as a compound that can inhibit the amyloid fibril formation of Parkinson’s-associated α-synuclein, but various physiologically relevant conditions can sig. reduce this ( to read more about this).
  • Researchers report real-Time 3D imaging & inhibition analysis of various amyloid aggregations (including Parkinson’s-associated alpha synuclein) using quantum dots ( to read more about this).
  • Researchers provide “useful information to understand the aggregation & cellular toxicity of pathogenic & non-pathogenic proteins”. 3 non-pathogenic proteins (BSA, catalase, & pepsin) compared with 3 pathogenic (lysozyme, SOD & insulin – to read more about this).
  • Could tremor in Parkinson’s be influenced by the cerebellum? Researchers report purkinje cell misfiring in the cerebellum generates high-amplitude action tremors that are corrected by cerebellar deep brain stimulation (in mice – to read more about this and click here to read the press release).
  • Researchers report the identification of region-specific astrocyte subtypes at single cell resolution. “Such insights might be important to our future understanding of regional susceptibility to diseases”, like Parkinson’s ( to read more about this).
  • The transcription factor Nurr1 is a target for Parkinson’s, with efforts to increase its levels. Now researchers report Nurr1 is up-regulated during early symptomatic phases in amyotrophic lateral sclerosis (ALS) patients & SOD1-G93A mice (Click here to read more about this).
  • Researchers report potential sources of interference with the highly sensitive detection & quantification of Parkinson’s-associated alpha‐synuclein seeds by qRT‐QuIC ( to read more about this).
  • Researchers report that the mutation rate in 2 human embryonic stem cell lines derived & banked for clinical application is low & not substantially affected by Rho Kinase inhibitor ( to read more about this).

  • HtrA2/Omi is a mitochondrial protein with homology to a bacterial heat shock protein. New research finds HtrA2 rescued an α-synuclein-induced Parkinson’s fly model by removing just oligomeric α-Syn. Bacterial function of HtrA evolutionarily conserved? ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that dopamine biosynthesis & synaptic vesicle recycling pathways were downregulated in dopamine neurons in both in MPTP mouse model & postmortem sections from Parkinson’s patients. Also genes critical for development & differentiation ( to read more about this).
  • A novel molecular mechanism for experimental Multiple Sclerosis treatment ibudilast – researchers report enhanced clearance of SOD1 & TDP-43 aggregates through TFEB-mediated autophagy & lysosomal biogenesis. Implications for Parkinson’s? (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting early stage Parkinson’s-associated α-synuclein pathology does not influence mitochondrial respiration in the striatum & amygdala, even in respirational hyperactivity ( to read more about this).

  • Researchers report an antioxidant berberine-derivative (Ber-D) that inhibits multifaceted amyloid toxicity associated with Alzheimer’s. Potential for Parkinson’s as well? ( to read more about this).
  • A screening study of a cross-kingdom collection of Hsp104 (a AAA+ protein disaggregase) homologs in yeast proteotoxicity models (including Parkinson’s-associated α synuclein) finds therapeutic genetic variations ( to read more about this).
  • Using optogenetic stimulation, researchers shed light (pun) on the functional contribution of motor cortex, subthalamic nucleus, & globus pallidus to cortico-basal ganglia neural dynamics in normal & Parkinson’s rodents ( to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that the C-terminus of Parkinson’s-associated DJ-1 is crucial for its homodimerization, deglycation activity & suppression of ferroptosis ( to read more about this).
  • Researchers report that binding of Parkinson’s-associated α-synuclein to the membrane simultaneously induces changes in the membrane topology, morphology, & fluidity, which prevents normal behavior of neurons & eventually neuronal death ( to read more about this).
  • Researchers have a bioRxiv suggesting that mice with the Parkinson’s-associated LRRK2 R1441C mutation display reduced nigrostriatal dopamine release & hypoexcitability in indirect-pathway striatal projection neurons. Further evidence that “the impact of individual LRRK2 mutations cannot be simply generalized” ( to read more about this).

 

Disease mechanism

  • In a mouse Parkinson’s model (nigral rAAV‐hSYN), CD200 k/o mice showed more dopamine neuron loss than wild type mice. Activation of CD200 receptors (via CD200 fusion protein) alleviated the neuroinflammation & neuronal death in WT PD mice (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that agonists of the morphogen Sonic Hedgehog (acting via Smoothened) attenuate L-dopa induced dyskinesias in mouse- & primate- models of Parkinson’s. Acute diminishment of Sonic Hedgehog being released from dopamine neurons (by optogenetic means) “in the otherwise intact brain & in the absence of L-Dopa results in LID-like abnormal involuntary movements” ( to read more about this).

  • Researchers report Pomalidomide – an FDA-approved Thalidomide derivative used for the treatment of multiple myeloma – is neuroprotective (via immunomodulation) in a drosophila LRRK2-WD40 model of Parkinson’s ( to read more about this).
  • Researchers report fatty acid-binding protein 3 (FABP3) ligand, MF8, inhibits dopaminergic neuronal death & improves motor/cognitive impairments in a mouse model of Parkinson’s (Click here to read more about this).
  • Japanese reseachers introduce BRUP‐1, an intracellular bilirubin modulator, that exerts neuroprotective properties in a cellular model of Parkinson’s. Also activates the Nrf2‐HO‐1 axis & increases bilirubin production (Click here to read more about this).
  • Researchers used Allen Brain Institute human postmortem brain datasets of non-neurological adults to identify expression patterns related to Parkinson’s progression (including PD GWAS genes: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, & SCARB2 – to read more about this).
  • Researchers report a role for Parkinson’s-associated PINK1 & Parkin in regulating mitochondrial biogenesis & health (via the PARIS/ PGC-1α axis). PARIS induced defects in mitochondrial biogenesis drive dopamine neuron loss without them ( to read more about this).
  • Researchers report agonism of the TrkB receptor, by the flavone 7,8-dihydroxyflavone alleviates motor symptoms & restores the loss of dopamine terminals within the striatum of an MPTP model of Parkinson’s (Click here to read more about this).
  • Researchers report an antioxidant-based nanotherapeutic candidate to target pathological protein aggregation & neuroinflammation in neurodegenerative conditions, like Parkinson’s ( to read more about this).
  • A novel probiotic formulation (SLAB51) has beneficial effects in in vitro & in vivo models of Parkinson’s ( to read more about this).

  • Researchers report oral treatments of Sphingosine-1-phosphate agonists (SEW2871 & Fingolimod) provided strong resistance to MPTP mouse model of Parkinson’s ( to read more about this).
  • Eigallocatechin‐3‐gallate (EGCG), the major polyphenol in green tea, exhibits Parkinson’s-associated PINK1 fly model. EGCG protection was blunted when gut microbiota was disrupted by antibiotics. Transcriptomic analysis identified TotM as the central gene ( to read more about this).
  • Researchers report that endogenous alpha synuclein level plays a key role in fibrillar prion-like seeding, supporting that alpha synuclein level participates in selective regional vulnerability in the Parkinson’s brain ( to read more about this).
  • Small study (6 Parkinson’s & 4 control postmortem brains) reports “different regions of the CNS were positive for a variety of microbial morphologies” in PD brains. Nested PCR analysis & next-gen sequencing identifies Botrytis, Candida, Fusarium & Malassezia genera ( to read more about this).
  • Ginsenoside Rg1 is one of the active ingredients in ginseng. Chinese researchers report Rg1 improves LPS-induced Parkinson’s symptoms in mice (via inhibition of NF-κB signaling & modulation of microglial M1/M2 polarization – click here to read more about this).
  • Ossianix Inc and collaborating researchers have a bioRxiv manuscript suggesting that a TrkB agonist antibody delivered to the brain (via a TfR1 specific BBB shuttle) provides neuroprotection in a mouse model of Parkinson’s (6-OHDA – to read more about this).

  • GBA-associated Parkinson’s is characterised by reduced activity in the enzyme Glucocerebrosidase (GCase). Now researchers report GCase activity modulation by 2-alkyl trihydroxypiperidines. Look forward to learning more about “compound 11a” ( to read more about this).
  • Human iPSC-derived microglia retain their identity & functionally integrate in the chimeric mouse brain, but report highlights differences in Parkinson’s-associated gene expression between humans & mice (eg Lrrk2 higher in human cells, GBA more in mice –  to read more about this).
  • Researchers compared brain homogenates from 6 idiopathic Parkinson’s, 1x familial PD & 6x multiple system atrophy (MSA) for their ability to induce a-synuclein aggregation. MSA samples were more potent ( to read more about this).

 

Clinical research

  • New report finds elevated mitochondrial DNA exclusively in serum from females with Parkinson’s (not CSF, & not in males). Also shows a lack of altered platelet mitochondrial methylation in people with PD (Click here to read more about this).

  • Using 23,224 hospital primary discharge diagnoses of Parkinson’s in Louisiana (1999–2012), allowed researchers to map cases against known crop distributions & pesticide use. The results don’t look good for paraquat producer Syngenta. Study conclusion: “In Louisiana, we have witnessed a major reduction in Parkinson’s disease incidence & distribution thanks to the introduction of glyphosate-resistant crops. Now, we need to firmly limit the use of 2,4-D, paraquat, & chlorpyrifos to prevent further cases” (Click here to read more about this).
  • Plasma cytokine concentration in people with GBA-associated Parkinson’s reveals elevated concentrations of IL-1β & TNFα (compared to controls & iPD cases – Click here to read more about this).
  • Validation of a Parkinson’s predictive model in a population-based study ( to read more about this).
  • A multicenter study with a 24 months follow-up, reports significant sustained improvements after bilateral subthalamic-deep brain stimulation using a Parkinson’s-specific sleep scale & a significant relationship between sleep & quality of life improvements ( to read more about this).
  • New population-matched study finds a diagnosis of stress-related disorders (PTSD, etc) is sig associated with greater risk of vascular neurodegenerative diseases, like Alzheimer’s, but not Parkinson’s or ALS, suggesting a potential cerebrovascular pathway (Click here to read more about this).
  • “Can boxing improve quality of life for people with Parkinson’s”? The preliminary result of a Rock Steady Boxing study have been released (not peer-review published): the study of 1,709 people with PD suggest “the outcome of this specific regimen seems particularly favorable” ( to read more about this).

  • A nationwide population-based study in South Korea reports anemia (low # of red blood cells) is associated with lower risk of Parkinson’s (particularly for patients with moderate to severe anemia). The “protective effect” is stronger in males than females ( to read more about this).
  • Researchers report an analysis of blood-based DNA methylation in 1132 Parkinson’s cases & 999 controls, identifying 2 DNA methylation probes associated with PD, & noting SLC7A11 as a plausible biological target. “SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, & it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA)” ( to read more about this & click here to read a press summary).
  • Researchers report that use of β2‐agonists does not appear to significantly affect subsequent risk of Parkinson’s in a real‐world chronic obstructive pulmonary disease (COPD) population (n=242,218 COPD patients, 732 PD cases – click here 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 ( to read more about this).
  • Researchers have a medrxiv manuscript suggesting no drastic changes in the spiking activity (discharge rate & pattern) of the striatal projection neurons of people with Parkinson’s (compared to dystonic patients – to read more about this).
  • An assessment of LRRK2 mutations & Asian disease-associated variants in the first Parkinson’s cohort (n=246 + 200 controls) from Kazakhstan. East Asian LRRK variants were apparent, but their pathogenicity remains to be elucidated in larger PD cohorts ( to read more about this).

  • Researchers report hemispheric differences in DNA methylation patterns are prevalent in neurons, & this could partly explain the asymetric affect on progression & symptoms of Parkinson’s. “It is possible that early-established diff.s in neuronal structure & survival, in combo with lifelong differences in immune activity & neurotransmission across hemispheres, lead to unilateral vulnerability, which may explain the corresponding unilateral presentation of Parkinson’s” ( to read more about this).
  • The Move Disorder Society Functional Movement Disorder Study Group surveyed to MDS members & found that “attitudes & management of functional movement disorders have changed over the past decade”, but “important gaps remain in the education of neurologists” (Click here to read more about this).
  • Researchers have a bioRxiv manuscript suggesting that mitochondria-mitochondria interaction networks differ in colonic ganglia from people with Parkinson’s (vs controls). “Patterns highly correlate with PD clinical scores” ( to read more about this).
  • Short‐chain fatty acids are exclusively produced by gut microbiota. Small study, but Korean researchers report that plasma short‐chain fatty acids are increased in Parkinson’s, & associated with disease severity & antiparkinsonian medications (Click here to read more about this).
  • Researchers report autonomic failure in Parkinson’s is associated with striatal dopamine deficiencies (n=310 PwP). Underlying mechanism requires further investigation ( to read more about this).
  • The Sleep Innsbruck Barcelona (SINBAR) Group report right-handed patients with isolated REM sleep behavior disorder exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction (Click here to read more about this).

  • Researchers report “Seeing ophthalmologic problems in Parkinson’s“. This multicenter questionnaire study, involving 848 people with PD found a higher prevalence of ophthalmologic symptoms (vs 250 controls), affecting daily living (Click here to read more about this).
  • Researchers conducted RNA‐sequenced transcriptomes of ~100 laser captured micro‐dissected substantia nigra neurons from each tier of 7 healthy controls. No Parkinson’s-associated genes differentially expressed ( to read more about this).
  • Under-represented parts of the Parkinson’s community – researchers provide insight on PD in the Middle East, North Africa, & South Asia (MENASA) regions (1/3 of the global population – to read more about this).
  • The same research also published a list of needs & priorities in the advancement of Parkinson’s in MENASA countries based on consensuses generated by the Movement Disorder Society Task Force for the Middle East, sheding light on unmet needs for people with PD ( to read more about this).
  • Researchers report that recessive loss of function mutations in ATP10B increase risk for Parkinson’s by disturbed lysosomal export of the lipids glucosylceramide & phosphatidylcholine ( to read more about this).
  • Longitudinal 5-yr serum uric acid measures in the Michael J Fox Foundation supported Parkinson’s Progression Markers Initiative (PPMI) database from 369 de novo idiopathic Parkinson’s patients did NOT differ statistically from 174 controls (despite a trend for lower uric acid in the PD group). No sex differences ( to read more about this).

  • Researchers have a bioRxiv manuscript using unsupervised data fusion to integrate morphometric, clinical & molecular information from 186 de novo Parkinson’s PPMI cases to generate multimodal biotypes & dimensions of PD ( to read more about this).
  • Researchers report epigenetic modification of PPARGC1A (the gene encoding PGC-1α) – specifically hypermethylation – in peripheral blood leukocytes in 171 people with Parkinson’s. No correlations btwn PPARGC1A methylation level & clinical features ( to read more about this).
  • The under-represented community: New study reports first confirmation from East Africa (Kilimanjaro, Tanzania) of PARKIN-related familial Parkinson’s ( to read more about this).
  • The under-represented community: Researchers provide a new study exploring the prevalence of GBA p.K198E mutation in Colombian & Hispanic Parkinson’s populations. They report a lower frequency than that observed previously ( to read more about this).
  • Sarcopenia (reduction in skeletal muscle mass) & Parkinson’s share common pathways & may affect each other’s prognosis & patients’ quality of life. New research in 218 PD patients reinforces “proper management of sarcopenia in PD patients is essential” (Click here to read more about this).
  • New report from the COPPADIS Study Group finds non‐motor symptoms burden is strongly correlated to motor complications in 690 participants with Parkinson’s (Click here to read more about this).
  • Higher vitamin B12 level at Parkinson’s diagnosis is associated with lower risk of future dementia (Click here to read more about this).

  • Lots of conditions share genetic associations. Researchers report a genome-wide association analysis of Parkinson’s & schizophrenia which reveals shared genetic architecture & identifies novel risk loci ( to read more about this).
  • Researchers have a medRxiv manuscript suggesting machine learning approach based on volumetric & diffusion tensor imaging data that can accurately classify individuals with early-stage Parkinson’s features (scanned on different MRI systems – to read more about this).
  • Researchers examined the Movement Disorder Society’s Parkinson’s Non‐Motor Rating Scale by factor & cluster analyses & found that “although each subscale is distinct in terms of content covered, factors & clusters that are of clinical relevance are discernible” (Click here to read more about this).
  • Researchers propose enhancing obstacle contrast to promote visual scanning in fallers with Parkinson’s. Gaze location is apparently associated with executive function & not visual function in PD (Click here to read more about this).
  • Researchers report a case-controlled association study that finds 2 variants in the intronic regions of the prosaposin (PSAP) saposin D domain (rs4747203 & rs885828) associated with sporadic Parkinson’s in a combined cohort from Japan & Taiwan (Click here to read more about this).
  • In a new medrxiv manuscript, researchers suggest that incorporating the previous intermediate markers of prodromal Parkinson’s & using likelihood ratios improved the accuracy of the PREDICT-PD prediction algorithm for PD ( to read more about this and click here to learn more about the Predict PD project).

  • Researchers provide evidence for an important role for the subthalamic nucleus in the circuitry underlying context-dependent modulation of visuomotor action selection, using a Parkinson’s deep brain stimulation cohort ( to read more about this).
  • Researchers report that changes in plasma arylsulfatase A levels could be considered a biomarker of “compensatory” mechanisms in early Parkinson’s. Elevated in early PD; correlated to the clinical & imaging markers ( to read more about this).
  • Researchers have a medRxiv manuscript suggesting that in contrast to observational data, “alcohol consumption causally increased risk of Parkinson’s”. Also higher BMI had a protective effect on PD, but the effect was small ( to read more about this).
  • Researchers suggest that recently reported MIDN/Midnolin deletions require further study before they can be unequivocally associated with Parkinson’s ( to read more about this).
  • Researchers report postmortem Lewy pathology (LP) in 85% of Parkinson’s cases (150/176 donors), 8% of atypical parkinsonian cases (8/101), & 25% of donors without a definite clinical diagnosis (4/16). LP associated with widespread amyloid-β pathology. “Classification of donors with LP based on the MDS-PD criteria only did not reflect differences in underlying neuropathology. Furthermore, amyloid-β was found to be associated with LP, suggesting a link between amyloid-β accumulation & LP formation” ( to read more about this).
  • Small study, but the ENGENE‐PSP Consortium report statins may have inverse associations with progressive supranuclear palsy risk. Type 1 statin users (simvastatin, lovastatin, etc) showed lower PSP risk & 1 yr delay in onset. Prospective studies required (Click here to read more about this).

New clinical trials

  • The Swedish Exenatide trial in Parkinson’s. Recruiting 60 participants; Phase 2 study; 18 months treatment of once weekly drug or placebo; Primary endpoint is brain imaging (FDG-PET – click here to read more about this).

  • Interesting new clinical study registered: An observational study exploring “Bringing Parkinson’s Care Back Home” has been in the Netherlands. 200 participants with an increased fall risk will use a remote monitoring systems at home (Click here to read more about this).
  • The results of the TANDEM investigation – assessting efficacy & tolerability of levodopa-carbidopa intestinal gel in cases of advanced Parkinson’s – finds that the approach is tolerable & safe (Click here to read more about this).
  • New clinical trial registered: Nestle are planning a 2 month pilot study in 2 groups of participants (Parkinson’s & Alzheimer’s), receiving 50g/day of Betaquik medium chain triglycerides supplement + aerobic exercise 3 times/week (Click here to read more about this).

  • Winner of best name 4 a clinical trial: The PADAWAN study (I kid you not). Researchers have registered the “Parkinson’s Disease – Adaptive Walking Assistance” (PaDAWAn) study to develop & validate a haptic assistive method to support walking (Click here to read more about this).

 

Clinical trial news

  • Theranexus announces their drug THN102 met the primary efficacy endpoint of its Phase 2 clinical trial by significantly reducing excessive daytime sleepiness in Parkinson’s ( to read more about this).
  • Neuraly has announced that they have dosed the first participant in their Phase 2 clinical trial of NLY01 – an exenatide-like GLP-1R agonist being developed for Parkinson’s (Click here to read more about this and click here to read a previous SoPD post about this drug).

  • Small pilot study explored tolerability of oral administration of scallop-derived ether phospholipids in Parkinson’s. 1 mg/day increased ether phospholipids in blood to almost normal levels after 24 weeks. Some clinical symptoms improved concomitantly ( to read more about this)
  • Prevail Therapeutics has provided an update on their clinical trial evaluating a gene therapy approach (PR001) for the treatment of GBA-associated Parkinson’s. Enrollment in Phase 1/2 PROPEL trial is progressing; on track to report interim data late 2020 ( to read more about this and click here to read a previous SoPD post on this trial).
  • Results of the OPTIPARK open-label study have been published – evaluating the effectiveness & safety of opicapone in Parkinson’s with motor fluctuations. 50 mg was effective and generally well-tolerated ( to read more about this).
  • Of the 15 Parkinson’s participants in the PD‐1101 clinical trial (evaluating Voyager Therapeutics gene therapy candidate VY‐AADC01), 13 participated in a substudy aimed at determining timing & magnitude of motor response to intravenous levodopa ( to read more about this).

  • Kainos Medicine asks US FDA to meet regarding their experimental Parkinson’s treatment KM-819 – a novel FAS-associated factor 1 inhibitor. The company is seeking to start Phase 2 trials in the U.S. based on their Phase 1 results in Korea ( to read more about this and click here to read a previous SoPD post on this drug).
  • IRL752 is a novel small‐molecule that acts to regioselectively enhance norepinephrine, dopamine, & acetylcholine transmission, being developed by IRLAB Therapeutics. Results of their Phase 2a safety/tolerability trial in Parkinson’s dementia have been published ( to read more about this).

  • Pfizer researchers report that PF-06649751 – a novel, oral, non-catechol-based, D1/D5 dopamine receptor partial agonist – was generally well tolerated in 15 week, Phase 2, double blind study of individuals with early stage Parkinson’s ( to read more about this).
  • Lundbeck reported headline results from Phase IIa AMBLED study of foliglurax – a positive allosteric modulator of the metabotropic glutamate receptor 4 – in Parkinson’s. The study did not show a statistically significant reduction in OFF time (primary endpoint) nor an improvement of dyskinesia (secondary endpoint). The development programme for foliglurax will be terminated (Click here to read more about this).

 

Other news

  • Applications are now open for the inaugural World Parkinson’s Congress Science Ambassadors Program. They are looking for basic and clinical scientists who embrace the WPC vision to bring the community together ( to read more about this).

  • Researchers are exploring the idea of a multi-arm multi-stage (MAMS) platform for clinical trials for Parkinson’s, discussing lessons learned from ther neurodegenerative conditions & cancer ( to read more about this).
  • Researchers shared an opinion piece drawing attention to the historical & continued importance of detailed & judiciously performed studies in single healthy volunteers or patients with unique clinical presentation, particularly Parkinson’s cases ( to read more about this).
  • Gene therapy company MeiraGTx reports that it anticipates filing an Investigational New Drug application (IND) for their AAV-GAD gene therapy treatment for Parkinson’s in the second half of 2020 ( to read more about this).

  • Researchers review the initiation of pharmacological therapy in Parkinson’s: the “when”, “why”, & “how” (Click here to read more about this).
  • Prevail Therapeutics announces that they will be presenting the preclinical data & Phase 1/2 clinical trial design of their gene therapy approach (“PR001”) for Parkinson’s with GBA1 Mutations at the AAT-AD/PD meeting this week ( to read more about this).
  • Prothena Corp announces that the baseline data from Phase 2 PASADENA study of their alpha-synuclein targeting immunotherapy “Prasinezumab” (PRX002/RG7935) in Parkinson’s will be presented at the AAT-AD/PD meeting ( to read more about this).

 

Review articles/videos

  • I don’t say this often, but everyone in the Parkinson’s community should watch this video:
  • Researchers discuss new insights on the structure of Parkinson’s-associated alpha-synuclein fibrils using cryo-electron microscopy, including possible implications of post-translational modifications, & a nomenclature system for fibril polymorphs ( to read more about this).
  • A useful review of cellular senescence in neurodegenerative diseases, including a section on Parkinson’s ( to read more about this).
  • Everything you need to know about exosomes in Parkinson’s: From pathogenesis, diagnosis, & treatment all the way through to prognosis ( to read more about this).
  • Small section on Parkinson’s in this review looking at the role of & potential therapeutic targeting of acid sphingomyelinase in aging and age-related neurodegenerative diseases. Further investigations of correlation btwn ASM levels & PD pathology required ( to read more about this).
  • A review exploring the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson’s ( to read more about this).
  • “A new threat to dopamine neurons: the downside of artificial light” ( to read more about this).

  • Researchers review recent advances in generating more complex human induced pluripotent stem cell-based systems using three-dimensional organoids, tissue-engineering, microfluidic organ-chips, & humanized animal systems ( to read more about this).
  • Researchers provide a useful review of the many different approaches that have been studied to inhibit Parkinson’s-associated α-synuclein accumulation (both direct & indirect targeting – to read more about this).
  • Researchers provide a useful exploration of the inheritance of mitochondrial DNA in humans: implications for rare & common conditions (like Parkinson’s – to read more about this).
  • Very interesting review on antisense oligonucleotides for neurodegeneration (Click here to read more about this).
  • A lot of young onset women ask about this, & finally there is a thorough report covering both a case study AND systematic literature review of pregnancy with Parkinson’s. A useful resource! ( to read more about this).

  • This review explores all aspects of Parkinson’s-asssociated alpha synuclein aggregation, including strategies to prevent formation of pathologic aggregates ( to read more about this).
  • Researchers explore the evidence linking Parkinson’s-associated Leucine Rich Repeat Kinase 2 (LRRK2) to the regulation of innate immune inflammatory pathways in this useful review ( to read more about this).
  • A mini-review of recent progress on α-synuclein proteostasis in the context of Parkinson’s ( to read more about this).

 

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

And there it is, just some of the highlights from March 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 April – be safe everyone!

 

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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.

2 thoughts on “Monthly Research Review: March 2020”

    1. Thanks for your comment Richelle – gad you liked it. And yes, encouraging to see all this research despite the current situation.
      Kind regards,
      Simon

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