At the end of each month, the Science of Parkinson’s writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available.
In this post we review some of the research from February 2018.
The post is divided into four parts based on the type of research (Basic biology, disease mechanism, clinical research, and other news).
Seeing shadows: Punxsutawney Phil. Source: Wordonfire
In major world event news: On the 2nd February of 2018, Punxsutawney Phil – the groundhog who resides at Gobbler’s Knob of Punxsutawney, Pennsylvania – scurried out of his little hole and saw his shadow. This omen indicates that we have a long winter. Given how hard and bitter this particular winter has been, Americans naturally rejoiced.
On the 6th February, SpaceX successfully launched a Tesla sports car into space – see the video below for the highlights (and if you don’t have time to watch it all, at the very least jump forward to 3:45 and watch the two boosters land simultaneously – surely they didn’t plan for it to be that perfect!)
In other news, on the 1st February, the Centers for Disease Control and Prevention announced that it was dramatically downsizing its epidemic prevention activities in 39 out of 49 countries, due to concerns about funding.
And of course we had the 2018 Winter Olympics – where New Zealand came in 27th on the medals board:
In the world of Parkinson’s research, a great deal of new research and news was reported.
In February 2018, there were 698 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (1577 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 PD news
1. Lewy bodies in mice? Lewy bodies are one of the defining features of the Parkinsonian brain, but we have very rarely ever observed them in models of Parkinson’s. New research suggests that the loss of autophagy (part of the waste recycling system) in dopaminergic neurons causes Parkinson’s-like Lewy bodies to appear, as well as dopamine cell loss and motor dysfunction similar to Parkinson’s in aged Atg7 conditional knockout mice. If independently validated, these mice could represent a fantastic new tool for testing novel PD-focused therapies as well as drugs for repurposing (Click here to read the research report and click here to read a SoPD post on this research).
A Lewy body inside a mouse brain. Source: Nature
2. Too much calcium? University of Cambridge researchers have found that the element calcium binds to one end of the Parkinson’s-associated protein alpha-synuclein which increases its lipid-binding capacity. They also found that calcium & alpha synuclein levels mediate dopamine toxicity and that the calcium channel blocker ‘Isradipine’ rescued cells from that toxicity – this is good news as Isradine is currently being clinically tested for Parkinson’s (Click here to read more about the research and click here and here to read more about the clinical trial).
Isradipine. Source: Dailymed
3. Increased risk of osteoporosis. Using the Korean National Health Insurance Database, South Korean researcher have found that people with Parkinson’s have a significantly increased risk of osteoporosis – a condition resulting in bone weakness (Click here to read more).
4. Inhalable levodopa almost here. The US FDA accepted a New Drug Application for INBRIJA™ (an inhalable form of levodopa) from Acorda Therapeutics. FDA has set a target date of October 5, 2018 for their decision of the approval of this product for clinical use (Click here to read the press release).
INBRIJA. Source: ParkinsonsLife
5. A genetic basis for Dystonia-Parkinsonism. Researchers from the Collaborative Center for X-linked Dystonia-Parkinsonism in Boston have used multiple genome & transcriptome assembly technologies to narrow down the causal genetic mutation of X-linked Dystonia-Parkinsonism to the TAF1 gene (Click here to read more about this).
Basic biology news
- Movement initiation is preceded by increased activity of dopamine neurons. Precisely timed (optogenetic) stimulation of dopamine neurons did not change ongoing movements, indicating a very specific role for dopamine activity in the initiation (Click here to read more about this research).
- Researchers have identified particular populations of neurons that generate different elements of a motor program involved in the maintenance of balance – implications for Parkinson’s? (Click here to read the research article)
The neurobiology of balance. Source: Cell
- New study suggests dopamine secretion is mediated by sparse, mechanistically specialised “active zone“-like release sites. When researchers genetically mutate one gene (called RIM) they find that the scaffolding of the site is disrupted and dopamine release is abolished (Click here to read more about this)
- Somatic mutations are genetic variants that occur during an organisms life time, rather than inherited. New research suggests brain somatic mutations accumulate with age (as much as one mutation per week in some regions of the brain), and accumulate faster in people with errors in DNA repair genes (Click here to read the research report and click here to read a SoPD post on the topic).
- Lots of research this month about the Parkinson’s-associated protein LRRK2, starting with the results of an experiment conducted on the international space station. Researchers were trying to look at the structure of the LRRK2 protein after it was grown in low gravity orbit. Unfortunately the results were no better than those achieved on Earth – back to the drawing board with this idea. A better understanding of the structure of LRRK2 will allow for better LRRK2-targeting drugs to be designed (Click here to read the manuscript and click here to read a SoPD post on this topic).
The International Space Station. Source: NASA
- Researchers also found that Parkinson’s-associated G2019S-LRRK2 gene mutation enhances striatal susceptibility to mitochondrial dysfunction induced by exposure to environmental toxins, & dopamine D2 receptor stimulation is neuroprotective on mitochondrial function (Click here to read more about this).
- Mouse models involving the LRRK2 G2019S genetic variant revealed that alpha synuclein pathology is LRRK2 kinase-dependent. Further evidence for the potential utility of a LRRK2 inhibitor? (Click here to read more about this).
- Greek researchers identify a domain within Parkinson’s-associated protein LRRK2 that mediates the interaction with cell death protein FADD. Disrupting the interaction between over-active mutant G2019S LRRK2 and FADD results in neuroprotection (Click here to read the abstract of this report).
- A screening study revealed that Rab GTPases are authentic substrates of Parkinson’s-associated LRRK2, particularly Rab35. Mutating LRRK2 sites on Rab35 induces neurotoxicity, suggesting that Rab GTPases might mediate LRRK2 toxicity in the progression of Parkinson’s (Click here to find out more).
- Parkinson’s-related LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without PD vs healthy controls & in LRRK2 mutation carriers with PD vs individuals with idiopathic PD (Click here to read the abstract of this research).
The structure of LRRK2 protein. Source: Wikipedia
- Researchers identify RAC1/Ced-10 as essential player in the regulation of dopamine neuron cell death AND Parkinson’s-associated protein alpha synuclein accumulation. RAC1 is necessary for autophagy (waste recycling inside of cells) to occur (Click here to read more about this research).
- Researchers have found that small heat shock protein, called Hsp27, that binds to Parkinson’s-associated alpha-synuclein fibrils, preventing their elongation & cytotoxicity effects (Click here to read the research report on this data).
- Glycation is a haphazard process that impairs the normal functioning of molecules. It results from sugars binding to proteins in an uncontrolled manner. The product is called an AGE (orAdvanced Glycation End product). These AGEs can have very negative effects of the body. New research suggests that LRRK2 interacts with AGEs. This interaction, however, may be particularly important for people with Parkinson’s-associated G2019S LRRK2 genetic variation. Novel drug target? (Click here to read this research report and click here to read an SoPD post on this topic).
- New research suggests that Parkinson’s-associated protein DJ-1 is involved with synaptic vesicle endocytosis (absorbing material into a cell at the point where signals are passed between cells). Thus, genetic mutations in the DJ-1 gene may be linked to the synaptic retrieval issues (Click here to read more about this).
- DOPAL is a toxic & reactive product of dopamine metabolism. DOPAL also cross links Parkinson’s-associated protein alpha synuclein. Researchers have identified Isoindole as a linkages that provides a pathway for DOPAL-mediated cross linking to alpha synuclein (Click here for more on this research).
- Researcher at the University of California, San Francisco have identify a subpopulation of neurons in the brain may mediate L-dopa-induced dyskinesia. They found that activation of these neurons produced dyskinesias even in the absence of L-dopa, and equally, inhibiting those same neurons reduced dyskinesias. This could represent an exciting new target for future treatments (Click here to read more about this).
- There was an interesting preprint manuscript on the website BioRxiv that involved the whole genome sequencing on 1.3 million people (!!!). The results implicate 956 genes involved in the sleep condition, insomnia. Interestingly, several Parkinson’s-associated genes pop up on that list – particularly SNCA (or Alpha Synuclein)! (Click here to read the manuscript).
Insomnia. Source: Hindustantimes
- In another BioRxiv preprint manuscript, researchers report that circulating unacylated-ghrelin is altered in the brain of people with Parkinson’s dementia, and it impairs memory in mice (Click here to read that manuscript).
- Researchers also found that reducing levels of ghrelin receptors on dopaminergic neurons in the substantia nigra causes Parkinson’s-like motor dysfunction in mice. Dopamine neurons with PARK2 genetic variant have less ghrelin receptors than controls (Click here to learn more about this).
- Another BioRxiv preprint manuscript reports that scopoletin, an active component in Morinda citrifolia (a tree in the coffee family) acts via DJ-1 mediated NRF2 signalling to protect the brain from oxidative stress in models of Parkinson’s (Click here to read that manuscript).
- Results from the IPDGC/COURAGE-PD study suggest that alpha synuclein His50Gln (H50Q) genetic variant is probably not a pathogenic variant in Parkinson’s (Click here to read more about this).
- Microglia are the resident form of active immune defence cells in the brain. New research shows that depletion of microglia (via the CSF1R inhibitor PLX3397) exacerbated locomotor impairment and dopamine cell loss in a model of Parkinson’s (Click here to find out more about this).
- Transcriptomic analyses reveals that MAPK/EGFR- & TGF-β signalling pathways were enhanced, while the Wnt signalling pathway was dampened in regulation of cell death & neuronal functions in fly model of Parkinson’s. Researchers found that restoring Wnt levels rescues the fly model (Click here to read more about this).
Drosophila (flies). Source: The Converstation
- Acrolein, a product of oxidative stress is elevated in models of Parkinson’s and can promote the aggregation of the protein alpha synuclein. Resarchers demonstrate that anti-acrolein scavengers (such as hydralazine) rescue the models of Parkinson’s (Click here to read more about this).
- Argentinian researchers found that Mdivi-1 inhibits Parkinson’s-associated protein alpha synuclein from inducing mitochondrial fragmentation (Click here to read more about this research).
- Naringenin, a citrus fruit flavanone, found to decrease alpha synuclein levels and inflammation in mouse model of Parkinson’s (Click here to read more about this).
- Korea researchers identify a molecular role of calcium and hard divalent metal cations in the accelerated formation and aggregation of toxic forms of Parkinson’s-associated alpha-synuclein protein (fibrils) (Click here to read more about this research).
- Lots of calcium research this month: Calcium-independent phospholipase A2β (iPLA2β) regulates important physiological processes including inflammation, calcium homeostasis and apoptosis. New research provides the structure of this Parkinson’s-associated protein suggesting mechanisms of action (Click here to read the research abstract).
- A non-selective but Calcium-conducting ion channel called TRPM7 that plays a critical role in the immune system cells response to inflammation. Could this be a novel therapeutic target for Parkinson’s (Click here to learn more about this research)
- Calcium channel blocker, Nimodipine, found to have neuroprotective properties in model of Parkinson’s. Results suggest that Parkinson’s might involve defects in regulatory proteins controlling calcium homeostasis, could be corrected by calcium channel blockers (Click here to read more about this).
Nimodipine. Source: Drugs.com
- Guanabenz, an antihypertensive drug (alpha agonist of the alpha-2 adrenergic receptor) promotes neuronal survival via enhancement of ATF4 & PARKIN levels in models of Parkinson’s (Click here to read more about this).
- New research suggests a novel mechanism for Parkinson’s-associated protein PINK1. It suppresses alpha synuclein-induced neuronal damage by promoting the dissociation of the calmodulin/Src complex and inhibiting Src, thereby enhancing PP2A activity (Click here to get the full story).
- Alpha synuclein protein aggregates also occur in the peripheral nervous system in Parkinson’s. But new research comparing brain aggregates with peripheral aggregates indicates that peripheral aggregates do not cause cell death! (Click here to learn more about this).
- Researchers have developed a virus that encodes a constantly active form of a protein called Rheb. Once it infects a cell, it induces the production of neurotrophic factors (such as GDNF & BDNF) and protects dopamine neurons in models of Parkinson’s (Click here to read more about this).
- New research suggests that Cilostazol (a phosphodiesterase-3 inhibitor) a medication for decreasing muscle pain/cramps, could be a promising candidate for Parkinson’s via modulating NURR1 levels, as well as SIRT-1/autophagy (Click here to read more about this research).
- Researchers have found that excess iron enhances Parkinson’s-associated alpha synuclein-induced neurodegeneration via alpha synuclein inhibition of Snx3-retromer-mediated retrograde recycling of iron transporters (Click here to learn more).
- An inherited form of Parkinson’s & dementia is caused by mutations in the OPA1 gene. OPA1-mutated cell cultures show reduced survival, but selective inhibition of necroptosis effectively rescues this survival deficit (Click here to read the research report).
- Variants in the psychosine degrading enzyme galactosylceramidase (GALC) gene are associated with Parkinson’s. Researchers have found that GALC mutations and prolonged exposure to increased psychosine could contribute to alpha synuclein pathology (Click here to read the full research report).
- Researchers found that Parkinson’s-associated protein alpha synuclein induces a distinct toxic species (oligomeric) of Tau protein that avoids the formation of fibrils (which were believed to be the toxic form of these proteins). Interestingly: Parkinson’s brain–derived alpha synuclein/Tau oligomers administered into a mouse model of PD accelerated endogenous Tau oligomer formation & increased cell loss (more than PSP-brain derived tau oligomers – Click here to learn more about this).
- Researchers found that a protein called cardiolipin on the mitochondrial surface binds to and facilitates refolding of Parkinson’s-associated protein alpha synuclein. Cardiolipin in alpha synuclein-mutant models starts recruitment of LC3 to the mitochondria & mitophagy (Click here to read more about this).
- Acoustic voice tremor analysis was conducted 30 people with Parkinson’s and 28 age-gender matched controls. Voice tremor was detected in both groups, but a statistically significantly higher rate of amplitude (which was negatively correlated with UPDRS III – Click here to read more).
- Aussie researchers demonstrate how axial rigidity & postural instability in Parkinson’s can be measured using wearable sensors. A small number of sensors can distinguish between variations in bradykinesia in subjects outside of the lab (Click here to learn more about this).
- A nationwide, population-based, retrospective cohort study in Taiwan suggests increased risk of Parkinson’s following tension-type headache (Click here to read the abstract of this research).
- National Institute of Health researchers proposed a new method for rapid and ultra-sensitive quantitation of disease-associated forms of Parkinson’s-associated alpha synuclein protein in brain and cerebrospinal fluid (technique called αSyn RT-QuIC – Click here to read more about it).
- New research suggests involvement of a region of the brain called the subthalamic nucleus in the propagation of tremor-related activity in Parkinson’s. Increased proprioceptive information flow during voluntary movement interferes with tremor generation (Click here to read the abstract).
- Micro changes in the cortex of people with early Parkinson’s were detected in a rich, multimodal MRI brain imaging dataset using linked independent component analysis (ICA), a novel data-driven technique (Click here to find out more about this research).
- An improved brain imaging tool suggests that at early stages of symptomatic Parkinson’s, a greater loss is observed at the level of the axonal terminals when compared with cell bodies of dopamine neurons (Click here to learn more about this).
- New research indicates selective cognitive impairment and hyposmia (loss of smell) in people with p.A53T SNCA-associated Parkinson’s (when compared with typical idiopathic PD – Click here to read the abstract of this study).
- In a new study of 196 drug-naïve people with Parkinson’s, 136 (69.3%) were categorised as coffee drinkers & 60 (30.6%) were non-coffee drinkers. Results showed that coffee drinkers had a lower severity in several non-motor symptoms (Click here to learn more).
- In a large study of 1,985 Israelis with pemphigus (an autoimmune skin condition), Parkinson’s was seen in 175 cases (8.8%) vs 437 controls (4.4% of a total of 9,874), indicating an association – these interesting results need independent replication (Click here to read the results of this study).
- The ENGENE-PSP case-controlled study found that any exposure to estrogen replacement therapy in women halves the risk of progressive supranuclear palsy (PSP) – similar to Parkinson’s. Future studies will be needed to confirm this association (Click here to learn more about this study).
- Better overall behavioural outcomes were noted with bilateral subthalamic deep brain stimulation plus medical therapy vs medical therapy alone for Parkinson’s with early motor complications (EARLYSTIM trial – an open-label randomised trial – Click here to read more).
- In other deep brain stimulation research, researchers found evidence of beneficial effects of bilateral subthalamic nucleus deep brain stimulation on non-motor features of Parkinson’s at 24-month follow-up (Click here to learn more).
Deep brain stimulation. Source: Spiegel
- Lysosome-associated membrane glycoprotein 2 (lamp2) is a protein involved in autophagy (waste recycling in cells). In a study of 108 subjects, Lamp2 levels were found to be decreased in females with LRRK2 associated Parkinson’s vs. control group (Click here to read more about this research).
- New research suggests that statistical parametric mapping procedure in conjunction with fluorodeoxyglucose-PET brain imaging could help in identifying people with Parkinson’s at risk of developing dementia (at the single-subject level! Click here to read more about this research).
- New biomarkers found in spinal cord fluid may help to differentiate Lewy body disorders (like Parkinson’s) from dementia conditions (like Alzheimer’s – Click here to read the abstract of this report).
- More on spinal cord fluid: can levels of dopamine in spinal fluid predict Parkinson’s? 26 people with PD risk factors (genetic, olfactory, dream enactment, orthostatic hypotension) were followed for 3 yrs. 4 were diagnosed with PD and 3 of the 4 had low DOPA & low DOPAC levels (Click here to learn more about this).
- Fecal markers of intestinal inflammation (Calprotectin) & intestinal permeability are elevated in subjects with Parkinson’s (vs age-matched controls – Click here to read more).
- Rapid eye movement sleep behaviour disorder may be associated with a genetic variant (rs3756063) located in the 5’ region of Parkinson’s associated protein alpha synuclein (the 3′ region of SNCA & the MAPT variant showed no association – Click here to read more).
- New research suggests that there are two distinct postural tremor phenotypes in Parkinson’s. They have different pathophysiology & require different treatment (Click here to read the abstract of this research).
- Idiopathic REM sleep behaviour disorder is considered a prodromal stage of Parkinson’s. New brain imaging study shows relative hypermetabolism in specific regions of the brain that partially overlapped with the pattern of people with PD (Click here to read more about this).
- Fractional anisotropy is a useful measure of connectivity in the brain. Fractional anisotropy values in the substantia nigra (where dopamine neurons reside) are significantly reduced in Parkinson’s & in cases of smell loss compared to controls (Click here to learn more).
Clinical trial news
- The new phase II clinical trial testing the safety & tolerability of the cancer drug Nilotinib in Parkinson’s is now recruiting (Click here to read more about this and click here for a SoPD post on this topic).
- Herantis Pharmaceuticals is opening recruitment in their Phase 1-2 clinical study based in Helsinki (Finland) & Lund (Sweden) to evaluate the safety of the neurotrophic factor CDNF (Cerebral Dopamine Neurotrophic Factor) in people with Parkinson’s (Click here to read the press release).
- Biotech firms Eisai & Meiji Seika Pharma Co. announced the primary endpoint met in a Phase II/III clinical study of ME2125 (safinamide mesylate, “safinamide”) in people with Parkinson’s. Drug has multiple modes of action, including MAO-B inhibitor (Click here for the press release).
- First participants have been dosed in the Pharma TwoB Phase III multi-center, multinational study to determine the efficacy, safety & tolerability of P2B001 in early stage Parkinson’s – P2B001 is a combination of pramipexole & rasagiline (Click here for the press release).
- In January, pharmaceutical company Biogen dosed the 1st patient in their Phase 2 SPARK study of BIIB054 (a anti-alpha-synuclein antibody) in Parkinson’s – A multicenter, randomised, double-blind, placebo-controlled immunotherapy trial of PD (Click here for the press release).
- The US FDA approves Osmotica Pharmaceutical’s once-daily OSMOLEX ER™ (Amantadine) extended-release tablets for the treatment of Parkinson’s (Click here for the press release)
- A small pilot study of spinal cord stimulation for Parkinson’s found number of freezing-of-gait episodes reduced significantly from 16 (presurgery) to 0 (at 6 months post op) while subjects were on levodopa & off stimulation (Click here to read the research abstract, and click here to read a SoPD post on this topic).
An x-ray of the spine with a stimulator implanted (towards the top of the image, and cords leading off to the bottom left). Source:Wikipedia
- And finally, they may have dropped Parkinsons research, but the pharmaceutical company Pfizer has at least bucking the trend and published the clinical trial results for their Phase I study of the safety & tolerability of the novel Dopamine D1 Agonist (PF-06669571). “The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement”, meaning the drug was not superior to the Dopamine D1 agonists that are already available in the clinic (Click here to read the research abstract).
- The Parkinson’s institute (Sunnyvale) and the pharmaceutical company Merck have entered a collaboration to evaluate LRRK2 inhibition in preclinical models of Parkinson’s (Click here to read the press release).
- Alkahest Inc., a privately held biotech, has been awarded a grant from the Michael J Fox Foundation to support a clinical trial of GRF6019, a proprietary plasma-derived therapeutic for the treatment of Parkinson’s (Click here to read more).
These were the main Parkinson’s-related research highlights for the month of February 2018. 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).
I’m still playing with the style here regarding these monthly Parkinson’s research reviews – I fear that it currently reads too much like a shopping list, which would put anyone to sleep (well done if you are still reading!). Need to have a think about how to spice it up a little.
Any thoughts/feedback would be greatly appreciated (either in the comments below, or contact me directly).
And now on to March!
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.