# # # # 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 January 2023. The post is divided into 10 parts based on the type of research: Top 5 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 January 2023?

In world news:

January 1st – Croatia adopts the euro and joins the Schengen Area, becoming the 20th member state of the Eurozone and the 27th member of the Schengen Area.

 

January 10th – Researchers reported the discovery of a second potentially Earth-like planet in the TOI 700 system is reported using data from NASA’s Transiting Exoplanet Survey Satellite (TESS – click here to read more about this).

 

January 12th – Two groups of researchers present data in mice demonstrating the manipulation of the aging process (Click here to read more about this).

 

13 January – A study of ancient DNA supports or confirms that recent human evolution which led to increased resistance to infection of pathogens also resulted in increased risk of inflammatory disease in post-Neolithic Europeans over the last 10,000 years (Click here to read more about this and click here to read a press summary).

 

January 27th – This day was declared the wettest day on record for Auckland (New Zealand) with 258 mm (10.2 in) of rain exceeding the previous record of 161.8 mm (6.37 in). A “tropical atmospheric river” parked itself over the city and caused widespread catastrophic flooding:

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

In January 2023, there were 997 research articles added to the Pubmed website with the tag word “Parkinson’s” attached. In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. ASPro-PD study of ambroxol in Parkinson’s:

A large new Phase 3 clinical trial for the respiratory medication ambroxol has been initiated for people with Parkinson’s. And this is a big deal for us (& our supporters) at Cure Parkinson’s – there’s only 6 Phase 3 clinical trials for disease modification in Parkinson’s & we’re directly supporting 2 of them (Click here to read more about this). Going forward, Cure Parkinson’s is going to provide a OPEN ACCESS scientific justification for each of our major clinical trials – outlining the evidence & reasoning for each study – Click here for the one on initiating a Phase 3 study of ambroxol in Parkinson’s.

 

2.  Inhibikase publishes preclinical data: 

Inhibikase Therapeutics (with Johns Hopkins collaborators) present data in preclinical models of Parkinson’s of their brain-penetrant, oral c-Abl inhibitor IkT-148009 which is currently in clinical trial (NCT05424276). The data indicates that IkT-148009 is neuroprotective even when treatment began 4 weeks after initiation of the model (Click here to read more about this).

3.  The inhibition of CPT1: 

Researchers point towards inhibition of carnitine palmitoyl-transferase 1 (CPT1 – a regulator of key step in the metabolism of long-chain fatty acids) as a potential target in Parkin (PARK2)-associated Parkinson’s. They report that inhibition of CPT1 alleviates motor & non-motor issues in Park2 mutant mice (Click here to read more about this).

4.  Viral associations go viral:

Researchers identified 45 viral exposures significantly associated with increased risk of neurodegenerative disease in a large dataset, and then replicated 22 of these associations in a second large dataset. They replicated the previously reported association between Epstein-Barr & multiple sclerosis, AND they reported influenza and pneumonia were significantly associated with Alzheimer’s and Parkinson’s (Click here to read more about this).

 

5. The devil in the detail

The “bravery in science” award goes to a group of researchers in Hong Kong who presented the results of a randomized clinical trial of mindfulness meditation vs exercise in Parkinson’s, and they chose to present a timeline of major adverse events that occurred in their country during the study which may have affected the study (seriously, Figure 2 holds no punches – click here to read more about this).

 

Articles of general interest

• Nice piece from Elrica Tanu on her journey with Parkinson’s; “In 2023, my goal is the same as last year’s and the year before — to have the strength & courage to get up & keep going, no matter the challenges” (Click here to read more about this).

Basic biology news

• Researchers report a site-specific, reversible phosphorylation of the Parkinson’s-associated protein α-synuclein at Serine129 which occurs physiologically during neuronal activity; “Adds nuance to the interpretation of pS129 as a synucleinopathy biomarker” (Click here to read more about this).
• Excessive daytime sleepiness in a nonhuman primate model of Parkinson’s was improved by low-frequency stimulation of the pedunculopontine nucleus (Click here to read more about this).
• Researchers have discovered at least two mechanisms by which Parkinson’s-associated Parkin modulates glutathione metabolism; Could redox-based chemical readouts serve as a possible biomarker of progression? (Click here to read more about this).
• Researchers describe a protocol for α Synuclein seed amplification assays (originally αSyn-PMCA), which allows detection of α Synuclein aggregates in cerebrospinal fluid samples from Parkinson’s patients, dementia with Lewy bodies or multiple-system atrophy (Click here to read more about this).

• Identification of inhibitors of Parkinson’s-associated LRRK2 through computational drug repurposing highlights Abivertinib (Click here to read more about this).
• New research identifies “a critical molecular link between innate immunity & Alzheimer’s, & suggests that therapeutic targeting of the cGAS-STING pathway activity might effectively interfere with the progression of AD” – implications for Parkinson’s? (Click here to read more about this).
• Genetic deletion of nitric oxide synthase 2 reduces Parkinson’s-like pathology & neuroinflammation in a transgenic mouse model of synucleinopathy (Click here to read more about this).
• New research identifies YOD1 as a potential regulator in the NEDD4-α-synuclein pathway; Researchers report that deubiquitinating enzyme YOD1 deubiquitinates & destabilizes Parkinson’s-associated α-synuclein (Click here to read more about this).
• ADAR1: a mast regulator of aging & immunity – lots of recent research on a protein called RNA-specific adenosine deaminase 1 which regulates immune response & senescence (Click here to read more about this).
• Could defective NLRP3 palmitoylation be associated with Parkinson’s? Palmitoylation of NLRP3 at C844 is critical for preventing inflammasome activation; zDHHC12 directly palmitoylates NLRP3 & enhances its degradation through chaperone-mediated autophagy (Click here to read more about this).
• New biorxiv manuscript suggests “a novel aspect of lewy body morphogenesis, indicating the role of acetylated α-Tubulin in Parkinson’s“; Acetylated α-Tubulin accumulates in the neuronal cell bodies in subcortical structures at Braak stage 6 (Click here to read more about this).
• Nrf2 expression is decreased in brains of transgenic mice carrying Parkinson’s-associated LRRK2 variant; Also in LRRK2 overexpressing SH-SY5Y cells (Click here to read more about this)

• New research reports “that C/EBPβ/AEP pathway, aggravated by oxidative stress, is age-dependently activated and cleaves α-Syn N103 & regulates Lewy body-like pathologies spreading from the gut into the brain in human α-SNCA transgenic mice” (Click here to read more about this).
• Using a human A30P mutant α-synuclein expressing mouse, researchers report the appearance of olfactory deficits at 12–14 months of age, which was accompanied by the accumulation of α-syn pathology in projection neurons of the olfactory system (Click here to read more about this).
• New biorxiv manuscript suggests reduced progranulin increases tau & Parkinson’s-associated α-synuclein inclusions; Also alters phenotypes of tauopathy mice (via glucocerebrosidase – GCase – click here to read more about this).
• New data suggest that mutations in the TMEM175 gene may contribute to the pathophysiology of Parkinson’s; Impaired autophagic/lysosomal proteolytic flux and an increase expression of unfolded protein response markers in patient-derived fibroblasts (Click here to read more about this).
• Palmitoylation is essential for DNAJC5-induced α-synuclein secretion, & the secretion is not limited by substrate size or unfolding; DNAJC5 inhibitor quercetin led to a significant dose-dependent reduction in the secretion of endogenous α-syn (Click here to read more about this).
• Researchers “injected lysates of the intestine & vagus obtained from a diagnosed Parkinson’s patient, which contained abnormal α-syn aggregates, into the rat striatum unilaterally. Strikingly, such an injection” leads to neurodegeneration & α-syn deposits (Click here to read more about this).

• Neurotoxin DSP-4 dysregulates the locus coeruleus-norepinephrine system & recapitulates molecular & behavioral aspects of prodromal neurodegenerative conditions reminiscent of early Alzheimer’s & Parkinson’s (Click here to read more about this).
• New biorxiv manuscript suggests a diversity of underlying mechanisms across different genetic backgrounds, using Parkinson’s patient-derived GBA-N370S, LRRK2-G2019S & SNCA-A53T iPSC-derived dopaminergic neurons (Click here to read more about this).
• New biorxiv manuscript finds previously unknown mechanisms of mesencephalic astrocyte-derived neurotrophic factor (MANF) in regulating organelle homeostasis to treat autosomal dominant tubulointerstitial kidney disease (Click here to read more about this).
• New biorxiv manuscript presents the structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue (Click here to read more about this).
• Researchers capture & analyze the structural conformations of transient oligomeric species formed at the early stages of the self-assembly of Parkinson’s-associated α-synuclein with new nanoanalytical method (Click here to read more about this).

Disease mechanism

• Biotech firm Umecrine Cognition AB today announced results showing that the company’s clinical drug candidate golexanolone (allosteric GABAA-R modulator) reverses fatigue, anxiety, depression, & some cognitive & motor alterations in a model of Parkinson’s (Click here to read more about this).

• Immune modulation by Treg expansion (via CD28 superagonist CD28SA) at a time point of overt inflammation is effective in reducing α-synuclein pathology in a mouse model of Parkinson’s (Click here to read more about this).
• More research on the glymphatic system & the clearance of Parkinson’s-associated α-synuclein from the brain; AQP4 deficiency in mice increased α-syn pathology, loss of dopaminergic neurons, & PD-like symptoms; A53T-α-syn disrupts glymphatic system in mice (Click here to read more about this).
• Researchers used fiber photometry & optogenetic/ chemogenetic techniques to demonstrate substantia nigra dopamine neurons not only affect the response of STN neurons to movement, but also contribute to the enhancement of movement by STN stimulation (Click here to read more about this).
• Pharmacological characterization of the small molecule 03A10 as an inhibitor of α-synuclein aggregation for Parkinson’s (Click here to read more about this).
• Again, sex differences seen with CSF1R inhibitors – Multiple dosing paradigms in the Tg2541 tauopathy mouse model with CSF1R inhibitors cause a sex-independent reduction in pathogenic tau & reversion of non-microglial gene expression patterns (Click here to read more about this).

• Lithium just gets more interesting… Researchers explore whether lithium, trehalose, resveratrol & NAC (alone or in combo) alleviate behavioral & neurochemical impact of low-dose rotenone-induced mild mitochondrial dysfunction in mice (Click here to read more about this).
• The therapeutic peptide AmyP53 prevents amyloid pore formation driven by lipid raft microdomains of the plasma membrane; AmyP53 outcompetes Alzheimer’s-related Aβ1–42 binding to lipid rafts via a unique mode of interaction with gangliosides (Click here to read more about this).
• New research reports that upregulation of endogenous Glial cell line-Derived Neurotrophic Factor (GDNF) in the adult mouse striatum is not protective in a proteasome inhibitor lactacystin model of Parkinson’s (Click here to read more about this).
• Microglial depletion (via CSF1R-inhibitor PLX5622) exacerbates motor impairment & dopaminergic neuron loss in a 6-OHDA model of Parkinson’s; Microglial depletion reduces MeCp2 & Adora1 expression (Click here to read more about this).
• New research suggests that expression of neuronotypic GBA1-L444P may cause defects in the hippocampus – a mechanism by which cognitive decline is more prevalent in individuals with GBA1-Parkinson’s? (Click here to read more about this).
• New research describes the synthesis of C-nor-D-homo bile acid analogues & lagocholic acid derivative “7”; Treatment of Parkinson’s-related LRRK2-G2019S cells improves mitochondrial phenotype (Click here to read more about this).
• Vitamin B12 ameliorates the pathological phenotypes of multiple Parkinson’s models by alleviating oxidative stress (via reduced JNK phosphorylation & improved the mitochondrial biogenesis regulator PGC-1α – Click here to read more about this).

Clinical research

• New research reports age-dependent transcriptome-proteome decoupling in samples of Parkinson’s brains; “Results support the hypothesis that aberrant proteasomal function is implicated in PD pathogenesis” (Click here to read more about this).
• The GBA1-PD Browser – 371 GBA1 variants reported in Parkinson’s: 22 considered mild, 84 severe, 3 risk variants, & 262 of unknown status (Click here to read more about this).
• Could IL-17 producing γδ-T cells contributes to the development of an autoimmune reaction part of the Parkinson’s pathogenesis? New time-resolved RNA expression analyses of in vitro activated CD4+ T cells uncovers RNA expressional deregulation in PD (Click here to read more about this).
• New research investigates if individuals with Parkinson’s have a different response to changes in turning speed compared to unaffected older adults during 180° standing turns; Differences observed (Click here to read more about this).
• New research finds increasing of the cortical surface area in the olfactory cortex in early drug-naïve Parkinson’s patients & this was associated with abnormal cognitive function (Click here to read more about this).
• New study explores prediagnostic cognitive & functional trajectories in Parkinson’s in older women & men, & finds indications of cognitive & functional decline during the prediagnostic phase that exceeds rates associated with normal aging (Click here to read more about this).
• Gender differences in motor & non-motor symptoms in 199 individuals with mild-moderate Parkinson’s in the southeastern United States; “Men may experience worse PD-related quality of life & more depression than women” (Click here to read more about this).

• Vesicular acetylcholine transporter imaging in 101 non-demented people with Parkinson’s finds cholinergic basal forebrain morphometry is a robust predictor of regional cerebral vesicular acetylcholine transporter bindings, especially in the anterior brain (Click here to read more about this).
• A meta-analysis suggests that community-based exercise may benefit motor function in people with Parkinson’s. The most commonly used modalities of exercise were tango & tai chi, & the most common duration was 60 min twice a week (Click here to read more about this).
• Neuromelanin signal intensity has been reported to be reduced in all Parkinsonian disorders, except in Parkinson’s without RBD; “Moreover, the signal intensity was lower in multiple system atrophy than in isolated RBD & PD without RBD groups” (Click here to read more about this).
• A 3-years longitudinal investigation of uric acid levels among carriers of different GBA variants compared to sporadic Parkinson’s, genetic PD cohort, genetic unaffected cohort, and unaffected controls – data from the Michael J Fox Foundation’s PPMI study (Click here to read more about this).
• Is the clinical diagnostic accuracy of Parkinson’s improving? A new study wants to say yes, & “more marked at early stages of the disease” (Click here to read more about this).
• New research explores “how empirical & simulated whole-brain connectome-derived features can be utilized to classify patients with Parkinson’s against healthy controls in light of varying data processing & model validation” (Click here to read more about this).
• New research explores systems level analysis of sex-dependent gene expression changes in Parkinson’s; Results highlight dopamine metabolism (NR4A2), mitochondrial (NDUFA10, CA2) & lysosomal processes (CXCR4, SGSH – Click here to read more about this).
• New research suggests that Parkinson’s may affect the cerebral cortex in early & even preclinical stages of disease; Cortical thickness within the prefrontal cognitive control & medial temporal memory systems may differentiate PD patient cognitive progression (Click here to read more about this).

• New systematic review & network meta‐analysis finds “evidence of beneficial effects on the severity of motor signs & quality of life for most types of physical exercise for people with Parkinson’s”, but “the exact exercise type might be secondary” (Click here to read more about this).
• “A metagenomic meta-analysis of Parkinson’s shows consistent & novel alterations in functional metabolic potential & microbial gene abundance across 4 independent studies from 3 continents” – on the role of the gut microbiome in PD (Click here to read more about this).
• Identification of a possible proteomic biomarker in Parkinson’s; Discovery & replication in blood, brain & cerebrospinal fluid – “complement & coagulation cascades suggest a disease relationship to immune response” (Click here to read more about this).
• New research paper presents a systematic review & meta-analysis of gender differences in Parkinson’s prevalence, & find that differences may not be as stark as previously thought; Overall male/female prevalence ratio = 1.18 (Click here to read more about this).
• New paper identifies 3 structural variants associated with genetic risk of Parkinson’s, including a 2kb intronic deletion within the gene LRRN4 (Click here to read more about this).
• The Michael J Fox Foundation Global Genetic Parkinson’s Study Group: the largest international cohort of affected & unaffected individuals carrying PD-linked variants – what an amazing resource! (Click here to read more about this).

 

• New research explores dopamine transmission in aging, & finds a modest reduction of postsynaptic D2 receptor current amplitudes in nigral dopamine neurons in aged males, but most parameters were unaffected by age (Click here to read more about this).
• Mendelian randomization analysis reveals no causal relationship between plasma α-synuclein & Parkinson’s (Click here to read more about this).
• The results from a global burden of disease study have been published, exploring Parkinson’s in the Middle East & North Africa region, 1990–2019; “An upward trend was observed in the point prevalence of PD over the last three decades” (Click here to read more about this).
• Small study, but new results do not support a strong association of LIN28A with early-onset Parkinson’s among Japanese patients (Click here to read more about this).
• New research reports neurofilament light chain is increased in the parahippocampal cortex & associates with pathological hallmarks in Parkinson’s dementia; Combination of MRI & histological data suggests axonal stress (Click here to read more about this).
• Researchers report an association between C-reactive protein-albumin ratio & overall survival in Parkinson’s; Retrospective study indicates poor overall survival of PD patients is associated with the increase of C-reactive protein-albumin ratio (Click here to read more about this).
• New meta-analysis determines that compared to females, males with either Alzheimer’s or Parkinson’s have higher levels of homocysteine; Data from 3082 diagnosed patients (1162 males & 1920 females – Click here to read more about this).
• Researchers analysed skin biopsies from 3 locations in 31 patients with Multiple system atrophy & 54 with Parkinson’s; All MSA patients & 51/54 with PD had evidence of phosphorylated alpha-synuclein in at least 1 skin biopsy (controls=0 – Click here to read more about this).

New clinical trials

• New clinical trial registered: Researchers will evaluate the safety & potential benefits of methylphenidate as a symptomatic treatment for apathy in veterans with Parkinson’s; N=60 (Click here to read more about this).
• New clinical trial registered: A feasibility study of fMRI-neurofeedback in Parkinson’s; Participants will be shown their brain MRI activity in real-time & they will then use mental strategies, such as imagination to influence & regulate this activity (Click here to read more about this).
• New clinical trial registered: A 48-week Phase I study exploring safety & biomarker validation of sargramostim treatment in Parkinson’s; 10 participants are being recruited (Click here to read more about this).
• New clinical trial registered: FAScinate Therapeutics has initiated a Phase 2 randomized, double-blind, multiple dose study evaluating the safety, tolerability, PK & preliminary efficacy of KM-819 (FAF1 inhibitor) in 330 individuals with Parkinson’s (Click here to read more about this).

Clinical trial news

• A long-term follow-up (36 months) of focused ultrasound unilateral subthalamotomy in 32 individuals with Parkinson’s; “MDS-UPDRS III off-medication score was 22.9% lower at 3 years than before treatment” (Click here to read more about this).
• FAScinate Therapeutics completes Part 1a of Phase 2 study of company’s Parkinson’s drug candidate KM-819 – a FAF1 inhibitor; Part 1b will be a dose-finding study in PD patients; Part 2 of the study will be a 24-month trial (Click here to read more about this).
• “Exergaming, as applied in this study, showed to be feasible, safe & likely effective for the improvement of cognitive & motor functions of Parkinson’s inpatients”; N=40; The intervention was 5x/per week using Dividat Senso (Click here to read more about this).
• Small study (n=69), but researchers report combined metabolic activators improve cognitive functions in a Phase 2 trial of Alzheimer’s (NCT04044131 – which also involved Parkinson’s participants, but no mention in this report; Maybe that comes next? – Click here to read more about this).
• Results from a phase I/IIa, dose-escalation, open-label clinical trial of fetal midbrain precursor cells in idiopathic Parkinson’s assessing safety & efficacy; 15 participants received one of three different doses of cells & completed a 12-month follow-up (Click here to read more about this).
• “These findings support community choir as a feasible & scalable complementary approach to managing vocal production challenges associated with Parkinson’s” (Click here to read more about this).

Conferences/lectures

• The International Conference on Alzheimer’s and Parkinson’s Diseases will be held in Gothenburg (Sweden) between 28th March to 1st April.

• The 6th World Parkinson’s Congress will be held in Barcelona (Spain) between the 4th – 7th July. This event only happens once every 3 years, and brings together researchers, clinicians, patients, and the broader Parkinson’s community – a truly unique scientific meeting with something for everyone.

•  The 2023 Grand Challenges in Parkinson’s conference will be held on the 27th & 28th September at the Van Andel Institute in Grand Rapids, Michigan. The theme this year will be “Pathophysiological Mechanisms to Therapeutics” and the list of speakers is excellent.

Other news

• Neurocrine Biosciences & Voyager Therapeutics enter a strategic collaboration for the development/commercialization of Voyager’s preclinical, intravenously administered GBA1 gene therapy program for Parkinson’s & other gene therapies (Click here to read more about this).

 

• S.Biomedics has received regulatory approval for initiating a Phase 1/2a clinical trial of their embryonic stem cell-derived dopamine neural precursor cells for cell transplantation therapy in Parkinson’s (Click here to read more about this).
• IRLAB Therapeutics announced the top-line results from the Phase IIb dose-finding study of mesdopetam in people with Parkinson’s-related dyskinesia; It did not meet its primary endpoint (change in ON-time), but did reduce dyskinesias (Click here to read more about this).
• Annovis Bio have published the results of their dose-finding, biomarker study of buntanetap (known as Posiphen or ANVS401) in 14 early Alzheimer’s & 14 Parkinson’s patients; A Phase 3 for PD is currently recruiting (NCT05357989 – Click here to read more about this).

• Neurodex announces that it has received a grant from the Michael J Fox Foundation to develop a blood test for Parkinson’s stratification based on neuronal & oligodendrocyte derived extracellular vesicles (Click here to read more about this).
• Living Cell Technologies announces continued progress on its third clinical trial to assess NTCELL in people with Parkinson’s (in collaboration with Nzeno – Click here to read more about this).
• Interesting that the pharmaceutical company Eisai is exploring glucocerebrosidase (GCase) pharmacological chaperones for Gaucher disease & Parkinson’s (Click here to read more about this).
• Inhibikase Therapeutics announces the lifting of US FDA clinical hold on IkT-148009 in Parkinson’s; The company can now move forward with their 201 clinical trial (Click here to read more about this).

Review articles/videos

And there it is, just some of the highlights from January 2023 – 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 February!!!

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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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