# # # # 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 September 2022. The post is divided into 10 parts based on the type of research: Top 6 pieces of Parkinson’s news Articles of general interest Basic biology Disease mechanism Clinical research New clinical trials Clinical trial news Conferences/lectures Other news Review articles/videos # # # #

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So, what happened during September 2022?

In world news:

September 6 – Liz Truss was appointed Prime Minister of the United Kingdom after winning the July–September 2022 Conservative Party leadership election

September 8 – Queen Elizabeth II died at Balmoral Castle in Scotland at the age of 96. Her son Charles III succeeded her as King.

 

16th September – Mahsa Amini, a 22-year-old Kurdish woman died in an Iranian hospital days after being detained by the Government’s Guidance Patrol (or “morality police” ) for allegedly not complying with the country’s hijab regulations

 

26th September – NASA’s DART crashed into the asteroid Dimorphos and changed its course in a first test of potential planetary defense (do a google search for “Nasa’s Dart” and watch what happens – very clever!).

 

30th September – Russian President Vladimir Putin signs treaties absorbing the occupied regions of Donetsk, Luhansk, Kherson and Zaporizhzhia into the Russian Federation ( …and nobody paid attention)

 

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

In September 2022, there were 888 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (8884 for all of 2022 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. More data indicating that Terazosin reduces the risk of Parkinson’s

New data finds that men using Terazosin/doxazosin/alfuzosin have a somewhat lower risk of developing Parkinson’s than those using tamsulosin & a slightly lower risk than those using 5α-reductase inhibitors (Click here to read more about this).

2. Is the melanoma mystery solved?

We have known for a long time that people with Parkinson’s have a higher risk of developing melanoma and vice versa. But now researchers have identified an interesting connection. A new report finds that both endogenously produced DOPA & L-DOPA/carbidopa (the FDA-approved therapy for PD) inhibit the muscarinic acetylcholine receptor M₁ (CHRM1) in darkly pigmented melanocytes & this inhibits the growth of melanoma both in cell culture and in mice (Click here to read more about this and click here to read a previous SoPD post on this topic).

 

3.  Before everything else, mitochondria

New research provides an in-depth regional profile of the different stages of Parkinson’s in the brain. The findings highlight mitochondrial dysfunction as being detectable prior to neuronal loss & alpha-synuclein deposition (Click here to read more about this).

 

4.  PwPs: Parrots with Parkinson’s

Dogma: Only humans develop Parkinson’s-associated Lewy bodies.

New research: Scientists report widespread Lewy body-like pathology in Yellow-crowned parrot pedigree with a severe progressive early onset neurodegenerative phenotype (due to CADPS2 variants – click here to read more about this and click here to read a SoPD post on this topic).

 

5. A history of infections

Hospital-treated infections in early- & mid-life was investigated for its risk of Alzheimer’s and Parkinson’s later in life. A nationwide nested case-control study from Sweden found “Hospital-treated infections, especially in early- & mid-life, were associated with an increased risk of AD & PD“.  The results “suggest that infectious events may be a trigger or amplifier of a preexisting disease process, leading to clinical onset of neurodegenerative disease at a relatively early age“, but “the results do not formally prove a causal link” (this was an observational study only – Click here to read more about this).

 

6. Forget about wearables, think: “Invisibles”

Using radio waves from a wall mounted device, MIT researchers continuously monitored 50 participants, with & without Parkinson’s, in their homes for up to 1 year. The system could accurately track decline in gait and the effects of the COVID lockdowns (Click here to read more about this and click here to read a previous SoPD post about this topic).

Articles of general interest

• The “Modifiable Variables in Parkinsonism” (MVP) Study finding dietary & lifestyle factors associated with slower Parkinson’s progression (Click here to read more about this).

Basic biology news

• Researchers report in a mouse model of α-synuclein brain spreading, hyperactivity augmented & hypoactivity attenuated protein transfer; Key features: oxidative & nitrative reactions, accumulation of nitrated α-synuclein, & protein aggregation. Neuronal hyperactivity was associated with mitochondrial nitrative damage; Accumulation of nitrated α-Syn & protein spreading were reduced after suppression of neuronal activity; Enhanced SOD2 expression reversed hyperactivity-induced α-Syn spreading (Click here to read more about this).
• High-content phenotyping of stem cell-derived midbrain dopaminergic neurons from Parkinson’s patients using machine learning classification (Click here to read more about this).
• N-terminal acetylation of Parkinson’s-associated alpha-synuclein alters its aggregation behaviour. Highlights the complexity of the interaction of α-synuclein with lipid membranes (Click here to read more about this).

• “Win the Skin Immune System Trick” – Researchers present the WISIT vaccine platform & data for selected candidates that inhibit Parkinson’s-associated α-synuclein aggregation in a dose-dependent manner in vitro & in vivo (Click here to read more about this).
• “Direct neural reprogramming can be used for obtaining patient-derived dopamine neurons, which uniquely function as a cellular model to study age-related pathology relevant to idiopathic Parkinson’s” (Click here to read more about this).
• New research reports a feed-forward pathway that provides spatial control & membrane activation of Parkinson’s-associated LRRK2 kinase activity (Click here to read more about this).
• Deep characterisation of MODAG’s α-synuclein targeting small molecule anle138b which is being clinically tested in Parkinson’s; Anle138b binds in a cavity of lipidic α-synuclein fibrils (Click here to read more about this).
• New paper reports that the cryo-EM structures of α-synuclein filaments from the brains of individuals with Parkinson’s, PD dementia & dementia with Lewy bodies are made of a single protofilament; Different to MSA (Click here to read more about this).
• Researchers suggest that “a change in the lipid composition of cell membranes, which is taken place upon neurodegeneration, may trigger the formation of toxic protein species that otherwise would not be formed”; Implications for Parkinson’s? (Click here to read more about this).
• New research used GWAS of DNA methylation in neuronal population from Parkinson’s postmortem cortex, to find sex-specific changes in PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), NR4A2 (NURR1), & other genes (Click here to read more about this).

• New data identifies two new regulators of PINK1-dependent mitophagy initiation, KAT8 & KANSL1 (17q21), previously shown to modulate lysine acetylation; Could KANSL1 play a crucial role in “idiopathic” Parkinson’s? (Click here to read more about this).
• In a new report, researchers characterise the proteomes of ectosomes & exosomes; Their findings “suggest that EVs cargoes reflect core intracellular processes, & their functional properties might regulate basic biological & pathological processes” (Click here to read more about this).
• Posttranslational S-nitrosylation modifications: Regulating HMGB1 secretion & promoting its proinflammatory & neurodegenerative effects (via Mac1 interaction) in a model of Parkinson’s; Intranigral HMGB1 injection=PD features in WT mice (but not HMGB1 knockouts – click here to read more about this).
• Dopamine drives neuronal excitability in reward behavior (via KCNQ channel phosphorylation) – new insights into the role of dopamine in the brain (Click here to read more about this).
• Researchers present highly efficient generation of isogenic pluripotent stem cell models using prime editing (an editing system using a Cas9-nickase fused to a reverse transcriptase & an extended PE guide RNA). They applied this new tool to investigations of familial mutations associated with Parkinson’s (LRRK2 & SNCA – click here to read more about this).

• Researchers examine the distribution of α-synuclein oligomers in formalin-fixed paraffin-embedded brain samples from patients with Parkinson’s; Distribution of oligomers = more widespread than that of Lewy-related pathology (Click here to read more about this).
• New biorxiv manuscript points towards an early role of the peripheral immune system & the gut in LRRK2-G2019S mice – implications for Parkinson’s? (Click here to read more about this).
• Single-cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s highlights Fam241b, Emx2os, Bivm, Gm1439, Prdm15, & Rai2 (Click here to read more about this).
• The polypeptide Irisin is reported to prevent both the accumulation of Parkinson’s-associated α-synuclein & neuronal cell death in primary cell culture; Elevation of blood irisin levels in mice rescues intrastriatal α-Syn PFF model (Click here to read more about this).
• “Small soluble α-synuclein aggregates are the toxic species in Parkinson’s” – researchers find aggregates of WT α-synuclein <200 nm in length form during an in vitro aggregation reaction, cause inflammation. They also find small soluble α-synuclein aggregates in 3 Parkinson’s brains & they are more inflammatory (vs from 3 control brains); “3% more aggregates smaller than 50 nm in the PD samples, whereas aggregates larger than 100 nm in length are 1% more abundant in the controls”. “Hence, our study provides evidence that these small soluble aggregates are the critical species driving toxicity in the Parkinson’s brain” (Click here to read more about this).

• Researchers report stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation & toxicity of Parkinson’s-associated α-synuclein in vivo (A53T mice – click here to read more about this).
• New research highlights lipoprotein receptor-related protein 1 (LRP1) as a neuronal receptor for Parkinson’s-associated α-synuclein uptake & spread; In Lrp1-nKO mice the spread of α-synuclein was significantly reduced (vs WT littermates – click here to read more about this).
• Reearchers working on LYTL (“LYsosomal Tubulation/sorting driven by LRRK2”) identify the endoplasmic reticulum colocalizing with sites of fission of lysosome-derived tubules; Implications for Parkinson’s? (Click here to read more about this).
• New research indicates that the atypical Rab GTPase associated with Parkinson’s, Rab29, is localized to membranes; Rab29 is modified either by geranylgeranylation or by farnesylation (Click here to read more about this).
• Researchers report Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering & network dynamics (Click here to read more about this).
• New paper reports on identifying the optimal developmental age of human pluripotent stem cell-derived midbrain dopaminergic progenitors for transplantation in a rodent Parkinson’s model (Click here to read more about this).
• Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology & functional deficits in a mouse model of Parkinson’s/Dementia with Lewy bodies; The influence of aging related inflammation (particularly CSF2 –click here to read more about this).

Disease mechanism

• Air pollution & Parkinson’s: New research finds that fine particulate matter (≤2.5 μm in aerodynamic diameter [PM2.5]) can trigger the fibrillization of α-Syn & promote the formation of α-Syn fibrils with enhanced seeding activity & neurotoxicity in mice (Click here to read more about this).
• Chlorogenic Acid: New research indicates that the neuroprotective effect of this polyphenol (which is found in coffee) may involve GLP-1 secretion; Provides neuroprotection against a rotenone mouse model of Parkinson’s (Click here to read more about this).
• New research reports that Parkinson’s-associated LRRK2 impairs the physiological tetramerization of endogenous α-synuclein in human neurons; Both LRRK2 inhibitors & stearoyl-CoA desaturase inhibitor corrects tetramer:monomer ratio (Click here to read more about this).
• New research presents the discovery of azaspirocyclic 1H-3,4,5-Trisubstitued pyrazoles as novel, selective inhibitors of Parkinson’s-associated G2019S-LRRK2 kinase – with in vivo efficacy (Click here to read more about this).
• New research reports that Alterity‘s metal modulator AT434 (formerly PBT434) rescues pre-motor hyposmia in a mouse model of parkinsonism (the tau knockout (tau−/−) mouse – click here to read more about this).

• Investigators report ursolic acid enhances autophagic clearance & ameliorates motor & non-motor symptoms in mouse models of Parkinson’s (both in vitro & vivo – click here to read more about this).
• Researchers significantly reduced Parkinson’s-associated α-synuclein (oligomer) accumulation in the mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. “Long-term” was defined as 18 weeks (which in mice is apparently equivalent to ~13 human years – click here to read more about this).
• Network metrics, structural dynamics & density functional theory calculations identified a novel Ursodeoxycholic Acid (UDCA) derivative against therapeutic target Parkin for Parkinson’s (Click here to read more about this).
• Researchers from Mthera Pharma present MT101-5 (a herbal formula that consists of extract of Genkwae Flos, Clematidis Radix, & Gastrodiae Rhizoma); Treatment improves α-synuclein aggregation-induced motor dysfunction in a mouse model of Parkinson’s (Click here to read more about this).
• Feel the RAGE: New research reportst that Parkinson’s-associated α-Synuclein is a ligand of receptor for advanced glycation end products (RAGE), which mediates the binding of α-syn amyloid fibrils to microglia; RAGE inhibitor FPS-ZM1 mitigated neuroinflam (Click here to read more about this).

Clinical research

• Hypothesis: Disruption of subthalamic nucleus dynamics in Parkinson’s leads to impairments during walking. How do you test this? You build a neurorobotic platform embedding an isokinetic dynamometric chair! Results “expose key principles through which subthalamic nucleus dynamics encode walking, opening the possibility to operate neuroprosthetic systems with these signals to improve walking in people with Parkinson’s” (Click here to read more about this).
• New research reports glucose metabolism of the substantia nigra can distinguish individuals with neurodegenerative parkinsonian syndromes “from controls with good diagnostic accuracy & can be used as a marker of nigral degeneration” (Click here to read more about this).
• Researchers followed a group of Parkinson’s patients without dyskinesia at baseline for a maximum of 36 months & found that high Pittsburgh sleep quality index (PSQI) score is independently associated with an increased risk of dyskinesia (Click here to read more about this).
• Chinese sniffer dogs “may be a useful, noninvasive, fast, & cost-effective method to identify patients with Parkinson’s in community screening & health prevention checkups” (Click here to read more about this).

• Researchers report 371 GBA1 genetic variants associated with Parkinson’s (22 are considered mild, 84 severe, 3 risk variants, and 262 of unknown status), and they created a browser, containing up-to-date information on these variants – click here to read more about this).
• Researchers report that analysis of 24 studies (79 153 patients) indicates “a consistent association between long-term treatment with cholinesterase inhibitors & a reduction in all-cause mortality in patients with dementia” (Click here to read more about this).
• New study reports combining seed amplification assay & ELISA assays is a promising diagnostic tool for Parkinson’s, providing information about the disease stage by correlating with clinical measures of severity. Two independent human cerebrospinal fluid cohorts; Discovery (62 PD & 34 control) & validation (49 PD & 48 control); Levels of CSF seeded αSyn oligomers correlated with severity of symptoms of Parkinson’s as measured by UPDRS-3 (r= 0.58, p <0.001) & H&Y scores (r= 0.43, p <0.01 – click here to read more about this).
• A new paper reports the teaching of neural networks to predict the postural instability and gait disorder (PIGD) score of individuals with Parkinson’s from a single lumbar accelerometer (using 2 independent datasets – click here to read more about this).
• [18F]FBB PET imaging data from a cohort of 25 idiopathic Parkinson’s patients & 30 healthy controls from the Michael J Fox Foundation PPMI study suggests that beta amyloid clusters differently in PD (Click here to read more about this).

• Yesterday: the cerebellum has nothing to do with Parkinson’s. Today: “the basal ganglia, cerebellar & sensorimotor connector hubs are significantly involved in PD with their connectivity dysfunction potentially driving the clinical manifestations” (Click here to read more about this).
• New paper presents data on identifying protective drugs for Parkinson’s in health-care databases (using machine learning); Sulfonamide diuretics, in particular furosemide, showed the most robust signal (Click here to read more about this).
• A new paper reports that changes in dynamic transitions between integrated & segregated states may underlie visual hallucinations in Parkinson’s (Click here to read more about this).
• New research finds differential engagement of the basal ganglia during REM sleep & awake movements; Findings could “inform the development of DBS approaches tailored to suppress excessive movements generated during REM sleep in people with Parkinson’s” (Click here to read more about this).
• New research indicates that “bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability” (Click here to read more about this).
• A cross-sectional study explores diet quality, sleep & quality of life in Parkinson’s; Carbohydrates, protein, fruit & vegetable intakes were greater in PwP than population norms, but overall diet quality was low (Click here to read more about this).

• New study provides further data indicating that increased homocysteine levels were a risk factor for cognitive decline in Parkinson’s; No association was found between polymorphisms in genes involved in homocysteine metabolism & cognitive impairment in PD (Click here to read more about this).
• New results “are consistent with findings that not only mutant forms but also overexpression of the wild-type α-Syn protein lead to Parkinson’s & PD dementia & show a striking CSF α-Syn seeding profile, thus substantiating the role of RT-QuIC” (Click here to read more about this).
• Using electronic health records from the USA (OPTUM EHR), researchers report that metformin users compared with sulfonylurea users were associated with a lower risk of all-cause dementia, Alzheimer’s & vascular dementia but not with Parkinson’s or MCI (Click here to read more about this).
• New study analyzed impact of stress on Parkinson’s during the first phase of the COVID19 pandemic, comparing a “pandemic” group without infection (n = 79) but exposed to restrictions VS a “prepandemic” PD control group (n = 117); No difference in progression (Click here to read more about this).

• Researchers present functional network changes according to Parkinson’s motor subtypes starting from motor cerebellar networks (Click here to read more about this).
• Researchers suggest “research & trial designs for Parkinson’s should consider sex-specific differences, including across GBA variant severities”; Small study, but could be interesting if replicated over larger cohorts (Click here to read more about this).
• A meta-analysis review explores the question of which type of mind–body exercise is most effective in improving functional performance & quality of life in people with Parkinson’s; 60 RCTs, 2037 participants; Results highlight dancing! (Click here to read more about this).
• New research indicates that corneal confocal microscopy differentiates patients with Parkinson’s with & without autonomic involvement (Click here to read more about this).
• Astrogliosis is common with aging, but 1C-BU99008 (which targets the imidazoline type-2 binding sites of the astrocyte mitochondrial membranes) PET imaging cannot differentiate patients with Parkinson’s dementia from healthy controls of similar age (Click here to read more about this).

 

New clinical trials

• New clinical study registered: The New York Stem Cell Foundation Research Institute are seeking skin biopsies &/or blood cells from people with GBA-associated Parkinson’s for drug discovery projects (Click here to read more about this).
• New clinical trial registered: A Phase I drug-drug interaction study in 56 individuals has been initiated to assess the CYP1A2 & CYP3A4 interaction potential of TEV-56286 (aka: anle138b, which is being developed by MODAG for Parkinson’s – click here to read more about this).

Clinical trial news

• CuraSen Therapeutics has announced that the first participant has been treated with a novel combination therapy (CST-2032/CST-107) in Phase 2a study of mild cognitive impairment (MCI) or mild dementia due to Parkinson’s or Alzheimer’s. CST-2032 is an oral beta-2 adrenoceptor (β2-AR) agonist & CST-107 is a β-AR blocker, which will minimize known side effects of β2-AR agonists. The multi-center trial, which is expected to enroll approximately 40 patients, is being conducted in the United States & New Zealand (Click here to read more about this).

• I’ve heard of square dancing, but square stepping is a new one for me: A randomized controlled pilot study finds square-stepping exercise could be an effective intervention to improve executive function in people with Parkinson’s (Click here to read more about this).
• Australian biotech company Pharmaxis announced that they have received £2.9m from Parkinson’s UK to conduct a Phase 2 clinical trial of PXS-4728 (a SSAO/MAO‐B dual inhibitor) in isolated Rapid Eye Movement Sleep Behaviour Disorder (iRBD, a prodrome for Parkinson’s – click here to read more about this).

• The results of a Phase I/2 clinical trial involving the transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with Amyotrophic lateral sclerosis (ALS) have been published (Click here to read more about this).
• The Phase 3 CLARITY study reports significant reduction in clinical decline with Lecanemab in 1795 patients with early Alzheimer’s (Click here to read more about this).
• Results of a Phase I clinical study demonstrate the safety & feasibility of magnetic resonance–guided focused ultrasound putaminal delivery of intravenous GCase every 2 weeks in 4 patients with GBA-associated Parkinson’s (Click here to read more about this and click here to read a press summary of this research).
• Roche will be presenting Phase Ib clinical trial data for a “novel NLRP3 inflammasome inhibitor in early-stage Parkinson’s” at the 4th Inflammasome Therapeutics Summit on Thursday 1st December (Click here to read more about this).

• Also, Asha Therapeutics will be presenting a novel, brain-penetrant inhibitor of mitochondrial fragmentation that limits inflammation & rescues models of Parkinson’s on the first day of the meeting (Click here to read more about this).
• The protocol for the “Spinal cord stimulation therapy for patients with Parkinson’s & gait problems” (“STEP-PD”) study has been published; This will be an exploratory, double-blind, randomised, placebo-controlled feasibility trial following 14 patients (Click here to read more about this).
• A preprint of results of the Phase II, randomized, double-blinded, placebo-controlled clinical trial of Liraglutide in Parkinson’s is available (study funded by Cure Parkinson’s – click here to read more about this).

 

Conferences/lectures

• “Planning for Parkinson’s Prevention: A trial design forum” – really interesting hybrid conference in October focused on the next generation of clinical trials focused on actual prevention of PD – Boston, October 2nd & 3rd 2022 (Click here to read more about this).

Other news

• Interesting – QIAGEN & Neuron23 have announced a collaboration to develop a companion diagnostic for the biotech’s LRRK2 inhibitor, which is currently in the late stages of preclinical development for Parkinson’s (Click here to read more about this).
• Pretzel Therapeutics launched with $72.5 Million in Series A financing to pioneer therapies targeting mitochondrial dysfunction, in conditions like Alzheimer’s & Parkinson’s (Click here to read more about this).
• IRLAB Therapeutics announces that the last participant has been randomized for their ongoing Phase IIb study of lead candidate mesdopetam (IRL790; a dopamine D3 antagonist), being developed for Parkinson’s levodopa-induced dyskinesias (Click here to read more about this).

• The Unified Multiple System Atrophy Rating Scale (UMSARS): A status update, a critique, & a few recommendations (Click here to read more about this).
• Coave Therapeutics announces it has entered into collaboration with the Institute of Neurodegenerative Diseases at the University of Bordeaux to explore the development of gene therapy products targeting the transcription factor EB (TFEB) for Parkinson’s (Click here to read more about this).
• Amylyx Pharmaceuticals announces US FDA approval for the agent RELYVRIO (previously known as AMX0035 – a combination of sodium phenylbutyrate & taurursodiol) in the U.S. for the treatment of adults with amyotrophic lateral sclerosis ALS (Click here to read more about this).

 

Review articles/videos

And there it is, just some of the highlights from September 2022 – 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 October!!!

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You can do whatever you like with it!

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EDITOR’S NOTE: The author of this post is an employee of Cure Parkinson’s, so he might be a little bit biased in his views on research and clinical trials supported by the trust. That said, the trust has not requested the production of this post, and the author is sharing it simply because it may be of interest to the Parkinson’s community.

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.

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