Monthly Research Review – August 2018

~ 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 August 2018.

The post is divided into five parts based on the type of research (Basic biology, disease mechanism, clinical research, other news, and Review articles/videos). 

 

So, what happened during August 2018?

In world news:

August 1 – American technology company became the world’s first public company to achieve a market capitalization of US$1 trillion.

August 12th – NASA launched the unmanned ‘Parker Solar Probe’ which will study the Sun (up close and personal)

August 16th – Singer, song writer and pianist Aretha Louise Franklin passed away (sad day)

August 31st – Joe Giaglia, director of California Skateparks, who had previously made a x12.5 scale replica of a skate board finally got it certified by Guinness World Records as the largest in the world.

Seriously, it measures 35 feet, 7 inches long (10.8 meters)!

 

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

In August 2018, there were 679 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (5372 for all of 2018 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 5 pieces of Parkinson’s news

1. The Genetics of Parkinson’s

Researchers made available a report outlining a study in which they analysed DNA from 37,700 cases of Parkinsons & 1.4 million (!?!) controls and find 92 genetic risk factors for PD – 39 of them completely novel! Analysis of biological pathways associated with the data finds “6 annotations were related to vacuolar functionality and autophagy, 3 pathways for endosomal trafficking, 2 pathways for catabolism related functions, & 2 lysosomal pathways”. Despite all of this new data, however, these 92 genetic risk factors only account for less than 20% of cases of Parkinson’s ( to read more about this and click here to read a SoPD post on this topic).

 

2. Magnetic DBS?

Researchers announced the discovery of the ‘Electromagnetic perceptive gene’ (EPG) which they isolated from glass catfish. It encodes a protein that responds to electromagnetic fields. The researchers then inserted the DNA into motor cortex of rats and found that they could remotely induce motor evoked responses. Such technology could have big implications for deep brain stimulation of Parkinson’s in the future ( to read more about this, click here to read the press release, and click here to read a SoPD post on this topic).

3. Taking the  STING out of Parkinson’s

Researchers found that the removal of a protein called ‘Stimulator of interferon genes’ (or STING) reduces inflammation mediated by mitochondrial stress and protects mice with Parkinson’s assoicated genetic mutations (PINK1 or PARKIN). The researchers report that a strong inflammatory state in both PARKIN mutant mice and PINK1 mutant mice following exhaustive exercise (the mice ran until they could not run any more). Inflammation resulting from the exhaustive exercise was completely rescued by concurrent loss of STING. An interesting target for novel therapies? ( to read more about this and click here for an editorial on this report).

4. The Melanoma drug

In silico drug screening for PD (using genome-wide association study data) by Japanese researchers identifies 57 FDA approved drugs that could be useful for Parkinson’s. These drugs included dabrafenib – an anti-melanoma drug. The investigators then demonstrated that Dabrafenib could rescue both cell & mouse models of Parkinson’s. This result is interesting, because there is a curious connection between Parkinson’s and melanoma: People with Parkinson’s in general have a reduced risk of developing all known cancers except one – take a wild guess which one? People with Parkinson’s are 4 to 8 times more likely to have melanoma than people without Parkinson’s. So it is interesting that a melanoma-targeting drug displays beneficial effects in models of Parkinson’s (Click here to read more about this and click here for the press release).

5. Is Alpha Synuclein LRRKing around?

New research suggests that LRRK2, a Parkinson’s-associated protein, modulates the propagation & trafficking of another PD-associated protein: alpha-synuclein (via phosphorylation of RAB35). A new class of drugs (which are currently being tested) called LRRK2 inhibitors slowed the propagation in cell & animal models of Parkinson’s ( to read more about this).

Basic biology news

  • Reducing circulating transthyretin in microscopic worms (C Elegans) reduces protein aggregation-associated problems – a novel strategy for dealing with Parkinson’s & Alzheimer’s? ( to read more about this).
  • Researchers report that the truncation of one part of the Parkinson’s associated protein alpha synuclein can increase its tendency to aggregate at normal pH levels ( to read more about this).
  • Researchers report a new set of DJ-1 inhibitors with a defined mechanism of action that could have therapeutic benefits, & contribute towards the understanding of the biological function of the Parkinson’s-associated protein DJ-1 ( to read more about this).
  • New manuscript on biorxiv suggests that mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases. Implications for GBA-associated Parkinson’s? ( to read more about this).

  • Loss of glutamate signaling between the thalamus & dorsal striatum impairs motor function & slows the execution of learned behaviors, which could help to explain the bradyphrenia (slowness of thought) observed in some people with late stage Parkinson’s ( to read more about this).
  • If you take Parkinson’s-associated protein alpha synuclein from elephants, bowhead whales, & pigs, and then compare it with the human protein, what do you get? A small number of mutations that can significantly reduce alpha synuclein toxicity. Alpha synuclein from all three animal showed significantly reduced fibrillation behaviour. Elephant alpha synuclein formed much more oligomer, & pig alpha synuclein much less than human alpha synuclein ( to read more about this).
  • Dietary management along with physical activity has potential to improve mitochondrial biogenesis in flies with Parkinson’s-associated PARKIN genetic mutations ( to read more about this).
  • Accumulation of cholesterol & homocysteine in the nigrostriatal pathway of the brain contributes to the dopamine cell loss in mice – implications for Parkinsons? ( to read more about this).
  • New manuscript on biorxiv suggests severity of visual hallucinations in Parkinson’s is associated with marked alterations in structural network topology (reduction in connectivity strength across large network –   to read more about this).
  • Interesting new biodegradable hybrid inorganic nanoscaffold for stem cell therapy. Could this tech be useful in cell transplantation treatment for Parkinson’s? ( to read more about this).
  • Researchers conduct a wide range of assessments on mice with 2x normal GDNF levels, and they find improvements in motor coordination without any side-effects. Implications for Parkinson’s? ( to read more about this).

  • Deficiency of Parkinson’s-assocaited PARKIN gene suppresses skin cancer melanoma tumor development and metastasis (via inhibition of MFN2 ubiquitination –  to read more about this).
  • Point mutation in Elp6 gene causes Purkinje neuron degeneration & ataxia-like state in ‘wobbly’ mice. Protein misfolding similar to Parkinson’s. Potent & selective NLRP3-inhibitor MCC950 delays degeneration & onset of ataxia ( to read more about this and click here for the press release).
  • Interesting analysis of the effects of physiological metabolism, aging, & neurotoxin-stress on levels of oxidised Parkinson’s-associated protein DJ-1 (across different tissues –  to read more about this).
  • Researchers use clever toolbox to reveal distinct genetically defined dopaminergic pathways arising from the substantia nigra pars compacta. Implications for Parkinson’s? ( to read more about this).
  • Engineered gut bacteria rescue a metabolic condition in mice and primates. Given the theories of a ‘gut influence’ in PD, could there be a therapeutic angle for Parkinson’s here? (Click here to read more about this).
  • The recruitment of a protein called Arrestin to dopamine D2 receptor mediates locomotion but not incentive-based motivation – highlighting a novel pathway which could be therapeutically targeted for Parkinson’s ( to read more about this).
  • Late-onset Alzheimer’s and Parkinson’s are associated with genetic variations in autophagic and endolysosomal genes ( to read more about this).
  • Interesting new manuscript on biorxiv reveals a novel thalamo-subthalamic pathway involved in regulating movement initiation & demonstrates a circuit mechanism that could explain clinical efficacy of DBS in Parkinson’s ( to read more about this).

  • Aggregation of alpha synuclein – the hallmark of Parkinson’s – also occurs in various lysosomal storage conditions, like Krabbe’s disease. Researchers find that the glycosphingolipid psychosine promotes an open/aggregation-prone conformation of α-synuclein ( to read more about this).
  • Genetic mutations in a gene called Vacuolar protein sorting 35 (VPS35) are associated with late-onset Parkinson’s. Now researchers have engineered a VPS35 mouse with early synaptic dysfunction that could contribute to age-related issues seen in humans ( to read more about this and click here to read the press release).
  • The proteasome is a waste-recycling unit in a cell. Researchers have designed proteasome-directed nanobodies that selectively target Parkinson’s-associated alpha synuclein. This treatment reduces aggregation toxicity in a model of PD ( to read more about this).
  • Researchers find that THO protein complex coordinates movement of synaptic transcripts (RNA) from nucleus. Study shows THO proteins are critical for synapse development & dopamine neuron survival. Also weak association btwn genetic variants & Parkinson’s ( to read more about this).
  • Researchers find that Rspo2 is dynamically expressed during midbrain dopamine neuron development, & it increases dopaminergic neurogenesis & differentiation of human embryonic stem cells – implications for Parkinson’s? ( to read more about this).
  • Researchers demonstrate that Parkinson’s-associated alpha synuclein binds to DNA. At low protein‐to‐DNA ratio, the binding occurs as small clusters scattered along the DNA; at high protein‐to‐DNA ratio, DNA is fully covered by protein ( to read more about this).

 

  • Researchers implanted a device into the brains of mice, & when the first signals of a seizure were detected, delivered a native brain chemical which stopped the seizure from progressing. Obvious opportunities for Parkinson’s ( to read more about this).
  • Further evidence of the neuroprotective properties of exendin-4 (Exenatide) in a model of hypoxic-ischaemic encephalopathy. Exenatide is shortly going to be tested in phase III trials for Parkinson’s ( to read more about this).
  • Researchers isolated a Nurr1 fusion protein that demonstrates neuroprotective properties in models of Parkinson’s – their method of getting it into the cell is very clever ( to read more about this and click here to read the press release).

 

Disease mechanism

  • New evidence suggests that presenilin & Parkinson’s-associated PINK1 play important roles in the pesticide-induced neurotoxicity through the mechanisms involved in mitochondria-associated membranes ( to read more about this).
  • Short-term induction of GDNF rescued a model of Parkinson’s – using novel Adeno Associated Virus (AAV) “Gene Switch” vector (under the control of the approved small molecule drug mifepristone –  to read more about this).
  • Ganglioside lipids accelerate the formation of Parkinson’s-associated alpha synuclein amyloid aggregates (specifically, they induce conformational changes of alpha synuclein monomers & catalyse their aggregation at mildly acidic conditions –  to read more about this).
  • Researchers have discovered a potential early biomarker for neurodegenerative conditions, like Parkinson’s & Alzheimer’s. Activation of the integrated stress response induces production of a cytokine ‘Fgf21’ in the brain of neurodegenerative models ( to read more about this and click here for the press release).
  • Genetic mutations in the VSP13C gene have been associated with increased risk of Parkinson’s. New research finds that VSP13C binds the endoplasmic reticulum to late endosome/lysosomes & to lipid droplets, implicating defects in membrane lipid homeostasis ( to read more about this and click here to read the press release).

  • 14-3-3 proteins are chaperone proteins that interact with Parkinson’s-associated protein alpha synuclein & regulate protein trafficking. Researchers find 14-3-3θ reduces alpha synuclein cell-to-cell transfer & toxicity in models of PD ( to read more about this and click here to read the press release).
  • Postmortem analysis reveals elevated levels of inflammatory protein NLRP3 in dopamine neurons of people with Parkinson’s. Genetic analysis finds that variants in NLRP3 gene are associated with a significantly reduced risk of developing PD ( to read more about this).
  • Researchers have an interesting manuscript on biorxiv looking at the safety liability of LRRK2 kinase inhibitors for Parkinson’s. They found the inhibitors induce a reversible effect in the lungs of primates with no deficits. Interesting that even at low doses these inhibitors produce nearly complete inhibition of LRRK2 kinase activity in the brain (as assessed by levels of pS935-LRRK2 –  to read more about this).
  • Cell-penetrating artificial mitochondria-targeting peptide-bound to antioxidant protein metallothionein 1A alleviates damage in the mitochondria (the cellular power stations) in neurotoxin (MPTP) model of Parkinson’s ( to read more about this).
  • A glycoprotein called GPNMB is selectively elevated in the substantia nigra of people with Parkinson’s & increases after lysosomal stress. The increase may function to modulate the inflammatory response in PD ( to read more about this).
  • Researchers demonstrate that reduction of Parkinson’s-associated PINK1 or DJ‐1 impairs the movement of mitochondria in neurites. Interestingly they also suggest PINK1 mutant cells have reduced contacts between ER & mitochondria ( to read more about this).
  • New research demonstrates the importance of membrane binding, not only as part of the normal function of cells but also as an important step in the internalization & subsequent accumulation of Parkinson’s-associated alpha synuclein ( to read more about this).

  • Remove of the ‘Scarlet’ gene specifically within dopamine neurons in flies results in neurodegeneration & motor issues. Manipulation of the kynurenine pathway rescues situation by promoting synthesis of kynurenic Acid – implications for Parkinsons? ( to read more about this).
  • Researchers have found that silencing Nucleotide-binding oligomerization domain-containing protein (NOD)2 in microglia suppresses the inflammatory response induced in neurotoxin model of Parkinson’s. NADPH oxidase inhibitor Apocynin also rescues situation ( to read more about this).
  • Chinese researcher report that c-Abl directly interacted with GSK3β & catalyzed its phosphorylation. This interaction was enhanced in cell model of Parkinson’s. Imatinib (“Gleevec“) – similar to Nilotinib – was able to block this activity ( to read more about this).
  • Researchers report a link between heterozygous GBA mutations & impaired removal of mitochondria (mitophagy) both in cells & postmortem tissue from people with GBA-associated Parkinson’s ( to read more about this).

 

Clinical research

  • Can a brain imaging technique called substantia nigra sonography be used to differentiate between Parkinson’s & multiple system atrophy (MSA)? New research involving 200+ participants suggests ‘yes, but currently with low specificity’ ( to read more about this).
  • New research suggests the possibility that deep brain stimulation in early Parkinson’s may slow resting tremor progression ( to read more about this and click here for the press release).
  • New manuscript on biorxiv provides a mechanistic basis for understanding the Parkinson’s OFF state & also provides further conceptual link with network-level reconfiguration ( to read the manuscript).
  • Progressive Supranuclear Palsy (PSP) is a neurodegenerative condition, similar to Parkinsons. Researchers have found that the TRIM11 genetic locus is a genetic modifier of PSP phenotype ( to read more about this).
  • New pilot study suggests that spinal cord stimulation improves freezing of gait & anticipatory postural adjustment motor issues in people with Parkinson’s, but it failed to improve reactive postural responses ( to read more about this, and click here to read a SoPD post on the topic).
  • Researchers propose a new Magnetic Resonance Parkinsonism Index (MRPI 2.0) for differentiating progressive supranuclear palsy-parkinsonism from idiopathic Parkinson’s ( to read more about this).
  • Concurrent constipation, probable rapid eye movement sleep behaviour disorder & hyposmia (loss of sense of smell) found in 29.3% of Parkinson’s cases (vs 1.1% of controls) in a nested case–control study of US men (Click here to read more about this).
  • Individuals with 22q11.2 genetic mutations are at increased risk of developing early-onset Parkinson’s. A new mouse model of this genetic mutation finds that reducing the levels of alpha synuclein in these mice rescues the motor deficits ( to read more about this).
  • New clinical research suggests that retinal thinning is present in the early stages of Parkinson’s, correlates with severity of the condition, & may be linked to nigral dopamine cell loss. Retinal imaging may be useful for detecting changes in early PD ( to read more about this and click here to read the press release).

  • Atrophy in the Locus Coeruleus in Parkinson’s is unlikely to cause fatigue, but may be involved in mood & vigilance alterations ( to read more about this).
  • Analysis of 617 individuals with Parkinson’s finds that those with the highest genetic load (or the most genetic variants) were younger at diagnosis, but severity of clinical features were similar compared to patients with the lowest genetic load ( to read more about this).
  • Researchers propose using electrical activity recordings (local field potentials) of subthalamic nucleus to identify different motor subtypes of Parkinson’s ( to read more about this and click here for the press release).
  • Researchers have published a study evaluating the potential of self-reporting, web-based questionnaires to rapidly assess natural history & symptomology in genetically-defined Parkinson’s populations. Confirms previous findings ( to read more about this).
  • New study suggests that both open-loop (turning to the beat of a metronome) & closed-loop (turning with phase-dependent tactile biofeedback) cueing markedly improved turning in people with Parkinson’s ( to read more about this).
  • Alzheimer’s-related APOE ε4 is associated with severity of Lewy body pathology in dementia with Lewy bodies & Parkinson’s with dementia (independent of Alzheimer’s pathology). ε4 may be a modifier of processes that favor LB spread rather than initiating pathology ( to read more about this).
  • Analysis of 17,163,560 South Korean medical records suggests that components of metabolic syndrome (increased blood pressure, high blood sugar, excess body fat, & abnormal cholesterol) may be associated with increased risk of Parkinson’s ( to read more about this).
  • Analysis of a population-based dataset in Taiwan suggests no relationship between the use of pioglitazone (a PPAR-γ stimulator used in the treatment of diabetes) use and the incidence of Parkinson’s ( to read more about  this).

 

Clinical trial news

  • Denmark’s biotech firm Lundbeck is bringing a 3rd potential drug for Parkinson’s forward for clinical testing this year. Named ‘Lu AF82422’, this new drug is an antibody directed against the toxic form of alpha-synuclein. Phase I clinical testing starting soon ( to read more about this).
  • International Stem Cell Corporation recently began dosing the third cohort of their stem cell transplantation clinical trial for Parkinson’s. 12 individuals with moderate-to-severe PD will receive up to 70,000,000 neural cells ( to read more about this).
  • 15 patients who were treated with the Parkinson’s gene therapy treatment called ProSavin have been followed for up for >5 years. Significant improvement in OFF UPDRS part III motor scores seen at 2 years (n=14/15) & 4 years (n=8/15), compared to baseline ( to read more about this).

Other news

  • Fantastic idea! Edinburgh Univeristy is piloting “crowdlabbing” which allows 71-year-old Frances Taylor, (who was diagnosed with Parkinson’s 17 months ago) to help out in the research lab: “It is a desire to be helpful and to assist” she says. Gr8 attitude! ( to read more about this).

  • Cantabio Pharmaceuticals is to present positive efficacy results in a mice model of Parkinson’s for one of its orally administered novel DJ-1 protein targeting therapeutic drug candidates at the XXV International Symposium on Medicinal Chemistry ( to read more about this).
  • Very interesting blog post from Ben Stecher taking expert opinions on GBA associated Parkinson’s (Click here to read more about this).

  • A new Movement Disorder Society (MDS) criteria for clinically established de novo or recently diagnosed Parkinson’s has been published (estimated specificity was 95.4%, with 69.8% sensitivity, among 212 PD and 152 non‐PD patients –  if you would like to read more about this).

 

Review articles/videos

  • Interesting update on “Drug Repurposing in Parkinson’s” such as Ambroxol, Isradipine, Inosine, UDCA, Deferiprone, Exenatide, Nilotinib, & Simvastatin ( to read more about this).
  • Interesting review of a new hypothesis of Parkinson’s pathology (GTPase-p38 MAPK signaling & autophagy as convergence points of etiology & genomics –  to read more about this).
  • Latest blog post from the Parkinson’s Research Advocacy Group makes interesting reading for anyone interested in clinical research on Parkinson’s ( to read more about this).

  • Interesting opinion piece regarding crowd funding of unproven/controversial stem cell based therapies for conditions like Parkinson’s (Click here to read more about this).
  • Why transplant new cells into the brain, when we can just change the ones we already have? Interesting new review of the research surrounding the changing of cell types (transdifferentiation) for conditions like Parkinson’s ( to read more about this).

  • Interesting discussion about the hunt for useful biomarkers in Parkinson’s published calling for “biomarker-enriched design” in clinical trials ( to read more about this, click here to read the editorial, and click here to read a SoPD post on the topic).
  • Interesting article outlining the future of treatment for conditions like Parkinson’s using new technologies like virtual reality coupled with treadmill walking or cycling to help people with gait issues ( to read more about this).
  • Interesting discussion on the role of Parkinson’s-associated Pink1 & Parkin in mitochondrial stress, inflammation & neurodegeneration – commenting on the recent Sliter et al. (2018) in the journal Nature – #3 in the top 5 pieces of Parkinson’s research news at the top of this post ( to read more about this).

 

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

And there it is, just some of the highlights from August 2018 – 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 September!

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 – August 2018”

  1. Really well done again. Maybe an overload for some people but this is about the science – so you can’t “dumb” it down too much. There are people like me that don’t have the background nor time and or energy to digest it all, but we can still get a lot out of it. No suggestions – just affirmation. Just the pictures and text at the beginning are very entertaining!

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  2. Hi Simon,
    Do you have any knowledge of any additional research done on enterovirus theory of PD? I read your posts on the various research done in the past that considered virus pathogenesis nature of PD (thank you very much for the wonderful compilation of this information!) but it is this post https://f1000research.com/articles/7-302/v2 mentioned by you few months ago that really looked promising. I thought that it contained quite convincing evidence (14 out of 14 positives, evidence of virus activity in different stages, enterovirus antibody positive staining of all of the samples that came from PDP). Please correct me if I am wrong but it would be difficult to overestimate the importance of this study if indeed it is proven to be true! It certainly would explain a lot when it comes to Parkinson Disease and it would have huge implications for development of disease modification or disease preventing
    treatments (think polio!). After reading this publication I was curious if anybody ran enterovirus RNA RT-PCR test on CSF samples of PDPs. To my surprise I could not find any such studies. Am I missing something if I state that further investigation along the methods proposed by Dr. Dourmashkin et al. (including virus sequencing) is not just warrantied but should be pursued with urgency? I would truly appreciate your feedback.

    Thank you,
    Felix

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