Monthly Research Review – July 2019

EDITIORIAL NOTE: Apologies to readers for the lack of content on the SoPD website this month. At the Cure Parkinson’s Trust, we have been preparing dossiers for the Linked Clinical Trials meeting in August. I will explain this process and the initiative in a future post, but for now just understand that the preparation is a 7 days/week, 9am-2am marathon task – which has been left little time (or energy) for the SoPD.

In addition, I will be completely off the grid from the 1st August for 12 days, so expect further radio silence. No laptop. No phone (how will I survive?!?!). After that, we’ll be back to our regularly scheduled content (and a lot of catching up on recent research).

Kind regards, 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 July 2019.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 


So, what happened during July2019?

In world news:

1st-14th Juy – Wimbledon!

16th and 17th July – A partial lunar eclipse occurred. The Moon was covered about 65% by the Earth’s umbral shadow at maximum eclipse. This was the last umbral lunar eclipse until May 2021.

19th July – A week after cricketer Ben Stokes led England to beat New Zealand in an epic world cup final, some Kiwis nominated him for the New Zealander of the year award. Technically it works: He was born in NZ and lived there until he was 12, he apparently has Maori blood, and his parents still live there in NZ. Soooo… (Click here to read more about this).

31st July – concerns regarding the latest Ebola outbreak as the World Health Organization confirms a second person has died of the disease in Goma – a major transit hub in Democratic Republic of Congo (Click here to read more about this)

 

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

In July 2019, there were 782 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (5089 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. Over reacting in absence of PINK:

Canadian researchers demonstrated that when young mice who lack the Parkinson’s-associated PINK1 gene are infected with a particular bacteria, it caused inflammation in the gut, which led to the mice slowly developing Parkinson’s-like symptoms (normal mice recovered fine from the infection). These Parkinson’s feature reduce over time, but the results further add to a growing pile of data suggesting that the gut and environmental factors may be more influential in Parkinson’s than previously thought (Click here to read more about this and click here for the editorial)

2. Predicting dyskinesias

Dyskinesias are involuntary movements mainly associated with the long term use of Levodopa. A new research paper highlights clinical features of early Parkinson’s which are associated with increased risk of developing dyskinesias. The study involved the Oxford Discovery cohort of 734 people with Parkinson’s who were followed for up to 10 years since their diagnosis. Curiously, low mood and anxiety were predictive features of developing dyskinesias (Click here to read more about this).

3. Predicting PD onset with wearables

Data from longitudinal gait analysis (using wearables) suggests that we may be able to predict conversion to Parkinson’s. The TREND study reported that wearable technology assessing gait can discriminate future PD converters from unaffected individuals up to 4 years prior to diagnosis ( to read more about this).

4. Research to aid drug discovery

Researchers published a study assessing the association of marketed medications with risk of parkinsonism, using 4 large US claims databases (2181 drugs & 117,015,066 people). Reduced risk of parkinsonism was associated with Armodafinil (56% reduction), Modafinil (54%), Methylphenidate (39%) & the β-agonist Albuterol (17%). Of the β-blockers, only propranolol was associated with increased risk (32% increased risk). “Isradipine was associated with a decreased risk, but the results were heterogeneous & the sample sizes were small. When this heterogeneity was incorporated, the combined estimate showed no statistically significant association between the use of isradipine & parkinsonism” A guide for Parkinson’s drug discovery? ( to read more about this).

5. Alpha synuclein and lipoproteins
Researchers report that the co-occurrence of α-synuclein on lipoprotein vesicles, their uptake by dopaminergic neurons, & an increase of ApoE in early Parkinson’s, proposes a mechanism(s) for α-synuclein spreading. The increased levels of ApoE in cerebrospinal fluid (but not in plasma) from early PD patients (vs controls) occurs in 3 independent cohorts! The “data suggests that around 40 to 50% of CSF αSN is associated with ApoE-positive lipoproteins”. In agreement with previous studies, they find decreased levels of ApoAI in plasma (but NOT in CSF) from people with Parkinson’s. ApoAI was another one of the α-synuclein-interacting proteins in CSF ( to read more about this).

 

Basic biology news

  • Researchers provide evidence that the Parkinson’s-associated A30P α-synuclein mutation decreases subventricular zone cell proliferation (Click here to read more about this).
  • Dysregulation of 24(S)-Hydroxycholesterol has previously been associated with Parkinson’s. Now researchers report that 24(S)-Hydroxycholesterol can cause unconventional cell death via ER dysfunction & RIDD-mediated pro-death UPR signaling ( to read more about this).
  • Researchers report somatic & germline mutations in Parkinson’s-associated PARKIN impairs PINK1/Parkin-mediated mitophagy in lung cancer cells. They also report that the iron chelator, deferiprone, can induce mitophagy – all in cancer cells, but interesting ( to read more about this).

  • Researchers report that a mitochondrial matrix protein, MsrB2, plays an important role in switching on mitophagy (the removal of old mitochondria) via ubiquitination by Parkinson’s-associated Parkin & interacting with LC3 ( to read more about this).
  • Reducing CD33 levels rescued an Alzheimer’s mouse model (5xFAD mice), while knocking out TREM2 exacerbated the Aβ pathology. TREM2 acts downstream of CD33 in modulating microglial state in AD. Therapeutic possibilities – implications for Parkinson’s? ( to read more about this).
  • Researchers have a manuscript on BioRxiv demonstrating the unappreciated role of GABA uptake transporters & astrocytes in determining dopamine release in the striatum. Interesting issues in Parkinson’s model ( to read more about this).
  • Interesting report regarding the beneficial effect of Mucuna pruriens on oxidative stress in a fly model of PINK1-associated Parkinson’s ( to read more about this).
  • Researchers present data suggesting that Parkinson’s-associated PARK2 (PARKIN) mutations causes metabolic disturbances & impair survival of human iPS cell-derived neurons ( to read more about this).
  • Researchers report that the HRI/eIF2α/ATF4/HSPB8 signaling axis functions as a general mechanism for controlling protein misfolding, similar to the endoplasmic reticulum unfolded protein response. Implications for Parkinson’s? ( to read more about this and click here to read the press release)
  • New report provides data on a specific regulatory mechanism for Parkinson’s-associated LRRK2 (confirming that the kinase domain functions as a classical kinase which controls conformational dynamics in full-length LRRK2). Indicates therapeutic strategies ( to read more about this).
  • PTENα regulates endocytosis & modulates olfactory function. The report also identifies mutations in the N terminus of PTENα in people with Parkinson’s & Lewy-body dementia. Did someone say something about loss of smell??? ( to read more about this).
  • Mutations in genes associated with lysosomal (waste recycling) function are associated with Parkinson’s. Now researchers report that activation of the unfolded protein response of the endoplasmic reticulum can increase the activity of lysosomes (via XBP-1 – to read more about this).

  • Progressive dopamine deficiency reduces striatal cholinergic interneuron activity. Imbalance of acetylcholine over dopamine contributes to the motor deficit. Better acetylcholine-dopamine balance may improve motor function in Parkinson’s ( to read more about this).
  • Germfree mice or animals that receive antibiotics are unable to control viral replication within the brain leading to increased neuropathology. The microbiota of the gut protects against viral-induced neurologic damage via microglia-intrinsic TLR signaling (Click here to read more about this).
  • Type-1 reactions (T1R) are pathological immune responses in leprosy & can cause peripheral nerve damage. Researchers report that PARKIN & LRRK2 are 2 key inflammatory regulators. T1R & Parkinson’s may share overlapping pathways of pathogenesis ( to read more about this).
  • Researchers assessed NEAT1 levels in the subst. nigra of 53 brain donors (with & without Parkinson’s) & found elevated levels of NEAT1 in PD. Reducing NEAT1 enhanced cell death in a LRRK2-mediated manner; fenofibrate & simvastatin increase NEAT1 ( to read more about this).
  • Researchers emphasize the link between membrane trafficking defects & Parkinson’s: Endoplasmic reticulum exit machinery & ER-to-Golgi trafficking are markedly compromised in PARK20 cells, causing ER stress; PERK inhibition rescues cells ( to read more about this).
  • Researchers report the crystal structures of CD33, & that a sialic acid mimetic called P22 increases uptake of the toxic Alzheimer’s-associated β-amyloid into microglial cells. Therapeutic possibilities? ( to read more about this).
  • Using PARAPLAY, researchers find that Parkinson’s-associated DJ-1 is partially localized to the mitochondrial matrix. LRRK2 & α-synuclein do not exhibit intra-mitochondrial localization & localization does not change with cellular stress ( to read more about this).
  • Ubiquitin-specific protease 10 (USP10) has previously been reported to be induced aggresomes containing Parkinson’s-associated α-synuclein. Now researchers find USP10 is also a critical factor for Tau-positive stress granule formation ( to read more about this).
  • Researchers report that 5-Aminolevulinic acid combined with sodium ferrous citrate is effective in elevating OXPHOS, HO-1 protein, & mtDNA copy number: representing a promising therapeutic option for mitochondrial conditions (& maybe Parkinson’s? to read more about this).

  • Researchers have a manuscript on bioRxiv describing how PPM1H phosphatase counteracts Parkinson’s-associated LRRK2 signalling by dephosphorylating Rab proteins. Does anyone have any PPM1H activity enhancers? ( to read more about this).
  • Researchers present a brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase, which prevents the accumulation of neurotoxic metabolites. Implications for Parkinson’s? ( to read more about this).
  • New study reports that activating dp62 expression (in midlife) is an effective approach (in flies) to improve proteostasis & mitochondrial function &, thereby, prolong healthy lifespan. Knockdown of Parkinson’s-associated PARKIN reduces this effect ( to read more about this).
  • Researchers report an underappreciated role for the extensive cholinergic network, in which small populations of cholinergic interneurons can drive substantial changes in post-synaptic receptor activity across the striatum ( to read more about this).
  • Researchers have a manuscript on bioRxiv which questions the role for rare heterozygous or bi-allelic VPS13C mutations in late onset Parkinson’s ( to read more about this).
  • Researchers present their first study using long read sequencing with targeted capture of both the gDNA & cDNA of the SNCA gene in brain tissues of Parkinson’s, Lewy body Dementia, & control samples ( to read more about this).
  • New research suggests that that dopamine neurons derived from iPS cells collected from individuals with monogenic or sporadic Parkinson’s exhibit global DNA hyper-methylation changes ( to read more about this).

  • Researchers use multiple neuronal signals & analytical approaches in Parkinson’s patients & dopamine-depleted rodents to demonstrate that cortical β bursts are associated with highly stable cortical & basal ganglia phase locking ( to read more about this).
  • Parkinson’s-associated PARKIN negatively regulates necroptosis (by inhibiting RIPK1−RIPK3 complex formation) & tumorigenesis by inhibiting the necrosome – this regulation may serve as an important mechanism to fine-tune necroptosis & inflammation ( to read more about this).
  • Researchers report a novel molecular mechanism for quinone oxidoreductase (NQO1, a potent antioxidant) oscillation in Parkinson’s pathogenesis. Akt phosphorylates NQO1 at T128 residues & triggers its degradation. Time to inhibit Akt? (Click here to read more about this).
  • Dopamine-related basic biology: Researchers report that calbindin-D28K limits dopamine release in ventral but not dorsal striatum by regulating Ca2+ availability & dopamine transporter function (Click here to read more about this).
  • Parkinson’s-associated Alpha syn modulates DNA repair? Alpha-synuclein colocalizes with DNA damage response components within discrete foci in human cells & mouse brain. Removal of alpha-synuclein in human cells leads to increased DNA double-strand breaks. Alpha-synuclein knock-out mice show increased neuronal double strand breaks (DBS) – can be rescued by introducing human alpha-synuclein. Lewy inclusion-containing neurons in postmortem human tissue contain increased DSB levels. Authors propose a “model whereby cytoplasmic aggregation of alpha-synuclein reduces its nuclear levels, increases DSBs, and may contribute to programmed cell death via nuclear loss-of-function” ( to read more about this).

 

Disease mechanism

  • Researchers have a manuscript on BioRxiv reporting that that DNM3 & VAMP4 play a modest & independent role in determining age at onset in LRRK2-associated Parkinson’s ( to read more about this).
  • By combining a mouse model of misfolded protein injection & brain network model of misfolded protein diffusion, a new study “finds a link between the stereotypical spreading patterns of neurodegeneration, protein expression & anatomical connectivity” ( to read more about this).
  • Interesting manuscript on BioRxiv suggesting that cerebrospinal fluid sTREM2 levels could serve as a surrogate immune biomarker of neuronal injury in Parkinson’s that is associated with cognitive decline ( to read more about this).

  • Recently it has been shown in the large LEAP study that L-DOPA has no disease-modifying effect on Parkinson’s. But now researchers report that L-DOPA/benserazide has a suppressive effect on the propagation of pathological α-synuclein (in mice – to read more about this).
  • Researchers report that 10 kDa heat shock protein (HSP10) is a mediator of Parkinson’s-associated alpha synuclein-induced mitochondrial impairments in striatal synaptosomes ( to read more about this).
  • A manuscript on BioRxiv suggests that TMEM163, a gene associated with Parkinson’s, regulates zinc homeostasis by its efflux from cells (Click here to read more about this).
  • Researchers provide a really nice time course & magnitude analysis of alpha-synuclein inclusion formation/nigrostriatal degeneration in a rodent model of Parkinson’s (intrastriatal α-synuclein preformed fibrils – to read more about this).
  • Knockout of the Parkinson’s associated gene PARKIN (PARK2) causes large disturbances in the mitochondrial proteome of dopamine neurons ( to read more about this).
  • Interesting manuscript on BioRxiv on the role that Parkinson’s-associated LRRK2 plays in peripheral macrophages & brain-resident glial cells’ ability to respond to & express inflammatory molecules. LRRK2 KO mice can control a Mycobacterium tuberculosis infection, but they exhibit exacerbated lung inflammation & altered activation of glial cells in Parkinson’s-relevant regions of the brain. LRRK2 KO macrophages also have increased mitochondrial stress & altered metabolism ( to read more about this).

  • Researchers report abnormal mitochondria in a non-human primate model of MPTP-induced Parkinson’s. MPTP apparently induced shorter & abnormally distributed mitochondria, accompanied by the activation of dynamin-related protein 1 (Drp1 –  to read more about this).
  • Researchers have an interesting manuscript on BioRxiv demonstrating that the loss of acid sphingomyelinase rescues disease progression in a zebrafish model of Glucocerebrosidase (GBA1) deficiency. This is interesting given the association between GBA1 & Parkinson’s, but also because combined acid sphingomyelinase knockdown & GCase (the protein of GBA1) inhibition in human neuroblastoma cells unexpectedly lead to a decrease in monomeric α-synuclein ( to read more about this).
  • Lysosomal storage disorder-associated gene Arylsulfatase A has both pathogenic & protective mutations linked to Parkinson’s. Arylsulfatase directly interacts with α-syn, interaction of protective variant is more extensive, less with pathogenic variant. Arylsulfatase inhibited aggregation of α-syn in a dose-dependent manner, & reversed both cell & fly models of synucleinopathy. Collectively, the results suggest that Arylsulfatase is a genetic modifier of Parkinson’s pathogenesis, acting as a molecular chaperone for α-synuclein (Click here to read more about this).
  • Researchers have a manuscript on bioRxiv that reports kinase inhibition of Parkinson’s-associated G2019S-LRRK2 restores autolysosome formation & function to reduce endogenous alpha-synuclein intracellular inclusions ( to read more about this).
  • Corticobasal degeneration (CBD) can be clinically similar to Parkinson’s, but it has distinct tau protein pathology. A new report finds C9orf72 intermediate repeats are associated with CBD, increased C9orf72 expression & disruption of autophagy (Click here to read more about this).
  • A modified exosomes (with the neuron-specific rabies viral glycoprotein peptide) carrying an aptamer targeting α-synuclein aggregates found to reduce neuropathological deficits in a mouse model of Parkinson’s ( to read more about this).

  • Loss of midbrain dopamine neurons in Parkinson’s model results in reduction of autonomous subthalamic nucleus (STN) activity, which can be prevented by STN N-methyl-D-aspartate receptor (NMDAR) knockdown & reversed by ROS breakdown or KATP channel inhibition ( to read more about this).
  • Researchers report evidence that alpha‐synuclein pathology & dysregulation of monocytes in Parkinson’s may act together to induce excessive inflammatory responses ( to read more about this).

 

Clinical research

  • Researchers report the p.M393T variant in lysosomal gene TMEM175 as a risk factor for Parkinson’s. Normal TMEM175 protein reduced phosphorylated α-syn levels, while the p.M393T variant resulted in no change – “a rational therapeutic strategy for PD”? (Click here to read more about this).
  • Interesting pilot EEG-fMRI study of L-Dopa modulation of brain connectivity in people with Parkinson’s ( to read more about this).
  • “The first systematic analysis of stimulation parameters” from a large, controlled clinical trial (EARLYSTIM) of deep brain stimulation of the subthalamic nucleus for Parkinson’s ( to read more about this).

  • Researchers have a manuscript on BioRxiv which suggest that suppression of beta bursts (facilitated by neurofeedback training) could help improve movement initialisation in Parkinson’s ( to read more about this).
  • New manuscript on BioRxiv suggests that Parkinson’s-associated alterations of the gut microbiome could translate into functional differences affecting host metabolism & disease phenotype (147 PD+162 controls – to read more about this).
  • The PRIAMO study reports that an active sex life is associated with better motor & non‐motor outcomes in men with early Parkinson’s. I guess independent replication is required? (Click here to read more about this).
  • More evidence that α-synuclein interacts with lipoproteins. Using cerebrospinal fluid from 3 large, independent Parkinson’s cohorts, researchers demonstrate that APOE4 is elevated in early, drug naive patients with PD ( to read more about this).
  • Brain imaging of 118 individuals with Parkinson’s (52 cognitively normal; 46 mildly impaired; 20 with dementia) suggests that there are dynamic functional connectivity changes associated with dementia in PD ( to read more about this).
  • Basal tears from 93 people with Parkinson’s & 82 matched controls suggest that oligomeric alpha synuclein levels are significantly raised in PD in this easily accessed bodily fluid – a novel, noninvasive, inexpensive biomarker??? ( to read more about this).

  • Researchers present data highlighting “that MDS‐UPDRS change scores contain a substantial amount of error variance, underscoring the need for more reliable instruments to forward our understanding of the heterogeneity in PD progression” (Click here to read more about this).
  • A new study highlights features which should be able to help improve diagnostic accuracy of multiple system atrophy (MSAClick here to read more about this).
  • The genetic & clinico‐pathological profile of early‐onset progressive supranuclear palsy (PSP) – compared to late‐onset PSP & Parkinson’s (based on 33 early PSP, 328 late PSP & 2000 PD subjects – to read more about this).
  • Individuals with psoriasis showed a significantly increased risk of developing Parkinson’s in a nationwide study from Korea. Interestingly, systemic anti-inflammatory agents appears to reduce that risk ( to read more about this).
  • Impulse control behaviours occur in 19% of people with early Parkinson’s. A new paper on impulse control disorders in Parkinson’s and REM sleep behaviour disorder (RBD) found that RBD did not increase impulse control disorders. The primrary driver is thought to be dopaminergic medictaion ( to read more about this).
  • New research questions the performance of the MoCA, MMSE, & SCOPA-Cog tests for detecting cognitive decline in non-demented people with Parkinson’s over a 1-year interval ( to read more about this).

  • Researchers in the Netherlands are teaming up with Verily Life Sciences to conduct the Personalized Parkinson Project (PPP) – an unbiased, longitudinal approach to biomarker development. The published study protocol suggests 650 people with Parkinson’s to be recruited to take part in this study creating “a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in PD”. And you get the Verily Study Watch for 2 yrs! ( to read more about this).
  • Estrogen & PD: Postmenopausal women with drug-naïve Parkinson’s were divided into low (n = 31) or high (n = 31) estrogen exposure ratio groups. Low estrogen group had lower DAT in posterior putamen & ventral putamen than high estrogen group ( to read more about this).
  • Researchers report that blue light therapy glasses appear to have a positive effects on sleep, mood, & motor symptoms in Parkinson’s in this open label study ( to read more about this).

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  • Researchers report that atrophy of myenteric & submucosal neurons in Parkinson’s. 10/15 PD samples had a-syn deposits, None of the 10 controls showed any ganglionic degeneration or α-syn deposits ( to read more about this).
  • Meta-analysis of Parkinson’s-associated LRRK2-related cerebrospinal fluid studies finds that small sample sizes & methodological differences limit conclusions that can be drawn from these studies ( to read more about this).
  • A systematic review & meta‐analysis of in vivo α‐synuclein deposits in Parkinson’s, however, finds a very different result: “skin biopsy examination using anti‐phosphorylated α‐synuclein antibody has the best diagnostic accuracy” (Click here to read more about this).
  • Researchers report genetic analysis of Mendelian mutations in a large UK pop with Parkinson’s. Of the 2262 participants (424 with YOPD), 29 (1.4%) patients carried pathogenic mutations. 18 of them carried G2019S or R1441C LRRK2 variants ( to read more about this).
  • Locus coeruleus (LC) imaging holds promise for stratifying patients for clinical trials of noradrenergic dysfunction. Researchers present a consensus on how non-invasive in vivo assessment of LC integrity is progressing for Alzheimer’s and Parkinson’s ( to read more about this).

  • Researchers report results that provide information on the longitudinal assessment of peripheral inflammatory cytokines in Parkinson’s & give evidence that peripheral cytokines may have utility for aiding prediction of PD progression ( to read more about this).
  • Interesting write up about the protocol for a new study using N-of-1 tests to identify responders to melatonin for sleep disturbance in Parkinson’s ( to read more about this).
  • Levels of glucose-regulated protein 78 (GRP78) – a key mediator of the unfolded protein response pathway – are altered in the brain, but not in plasma or cerebrospinal fluid in people with Parkinson’s ( to read more about this).
  • Analysis of 13 longitudinal Parkinson’s cohorts assessed genetic risk of Parkinson’s and it’s progression (Click here to read more about this).
  • Longitudinal analyses (36‐months) of cerebrospinal fluid α‐synuclein in prodromal & early stage Parkinson’s (using the Michael J Fox Foundation funded PPMI database) finds CSF α‐synuclein doesn’t correlate with progression & therefore doesn’t reflect ongoing neurodegen ( to read more about this).

 

New clinical trials

  • Interesting new clinical study has been registered for “learning effective new strategies for worry in Parkinson’s” (or LENS-PDClick here to read more about this).
  • Prevail Therapeutics has announced that they have received FDA Fast Track Designation for their gene therapy candidate PR001 for the treatment of GBA-associated Parkinson’s. Fast Track designation is a process designed to facilitate the development & expedite the review of product candidates to treat serious conditions & fill an unmet medical need. Fast Track designation allows for early & frequent communication with the FDA throughout the process ( to read more about this).

 

Clinical trial news

  • Cerecor announces positive Phase I results of CERC-301 in the treatment of neurogenic orthostatic hypotension (OH). CERC-301 is an orally available, NR2B-specific, NMDA receptor antagonist being developed for the treatment of symptomatic OH in Parkinson’s ( to read more about this and click here for the press release).
  • Pharmacokinetics & tolerability of PureIMS’s Cyclops® (inhaled levodopa from a new dry-powder inhaler) in people with Parkinson’s. Well tolerated, absorbed faster than oral levodopa, & does not require loading of capsules (contrary to CVT301/Inbrija –  to read more about this).
  • A randomized controlled clinical trial was conducted to investigate the impact of Tango Argentino versus Tai Chi on quality of life in Parkinson’s. Can you guess which won? ( to read more about this).
  • Epigallocatechin gallate treatment did not modify disease progression in patients with multiple system atrophy (Click here to read more about this).
  • Small 6 week clinical study finds that exergaming is an easy-to-apply, safe technique, which can improve deficits in cognitive-motor dual-tasking & attention in Parkinson’s. Anyone for “Virtual smash” or “Kardio boxing”? ( to read more about this).
  • Intec Pharma announced top-line data from their pivotal Phase 3 trial (the ACCORDANCE trial) evaluating the safety & efficacy of the Accordion Pill®-Carbidopa/Levodopa (AP-CD/LD). The study was not statistical superior to Sinemet on the primary endpoint (Click here to read more about this).
  • Scion NeuroStim & researchers from the University of Kent have published a report investigating whether caloric vestibular stimulation relieves Parkinson’s symptoms. 33 participant; double-blind, placebo-controlled, randomized study; & gains were still evident 5 weeks later! ( to read more about this).
  • The results of an open label clinical trial assessing pharmacodynamics & safety of IPX203 – extended-release carbidopa-levodopa combination – in Parkinson’s with motor fluctuations have been published ( to read more about this).
  • AbbVie calls off a Phase 2 trial of its anti-tau antibody ABBV-8E12 for progressive supranuclear palsy (PSP) due to lack of efficacy ( to read more about this).

 

Other news

  • Biotech Seelos Therapeutics has announced the exclusive worldwide licensing of a gene therapy program targeting the regulation of the SNCA gene, which encodes the alpha-synuclein protein, from Duke University. This is a potential therapy for Parkinson’s. The experimental treatment (called SLS-004) is “an all-in-one lentiviral vector, for targeted DNA-methylation editing within intron 1. The system is based on CRISPR-dCas9 fused with the catalytic domain of DNA methyltransferase 3A (DNMT3A)” – a DNA methylation enzyme ( to read more about this).

  • Dundee Univiersity & Bukwang Pharma join forces to focus on USP8 inhibition for Parkinson’s (Click here to read more about this).
  • Parkinson’s UK has launched a new research project via their Parkinson’s Virtual Biotech. They are investing nearly £1 million to find a new treatment with NRG Therapeutics Ltd that targets mitochondrial function (the power stations of cells – to read more about this).
  • Parkinson’s Foundation & Fulgent Genetics have announced a collaboration on a new genetic testing initiative for individuals living with Parkinson’s. The nation-wide initiative, called “PD GENEration: Mapping the Future of PD” ( to read more about this and click here to see the website).

  • Go kiwis! The Michael J Fox Foundation awards a major research grant to NZ researchers to investigate ways of delaying the onset of Parkinson’s. This research will be a follow up on their previous work (Click here to read that research) looking at pericytes (cells that line the blood vessels throughout the brain). They will look at the alpha synuclein induced inflammatory response in pericytes & test pericyte anti-inflammatory compounds ( to read more about this).
  • Dante Labs launches first whole genome reports powered by artificial intelligence (one hopes the “personalized reports” are provided via genetic counselling – Click here to read more about this).
  • Members of Critical Path for Parkinson’s Consortium have published a review of the qualification of an enrichment biomarker for clinical trials targeting early stages of PD. All about SWEDDs (Scans without evidence of dopaminergic deficit – to read more about this).

  • The Michael J Fox Foundation has set up a strategic funding & enabling framework to bring together the research community to support collaborative initiatives in Parkinson’s-associated PINK1-PARKIN biology to further our understanding of this field ( to read more about this).
  • The UK MS Society and Parkinson’s UK are set to invest £3 million into a new UK ‘digital brain bank’ – Europe’s largest brain & tissue bank, based in London (“complete with virtual reality interface” – oohhh). Sounds amazing! (Click here to read more about this).

 

Review articles/videos

  • From dreams to parkinsonism: tracking the journey. New commentary by Prof Michele Hu ( to read more about it).
  • A useful review of neuroinflammation & glial phenotypic changes in alpha-synucleinopathies like Parkinson’s ( to read more about this).
  • Interesting overview of Parkinson’s biomarkers based on alpha‐synuclein ( to read more about this).
  • Interesting video of Prof Lorenz Studer discussing stem cell-derived cell transpantation for Parkinson’s:

  • “The physiological role of α‐synuclein & its relationship to Parkinson’s disease”, by David Sulzer & Robert Edwards. If synuclein is important to synaptic transmission, why does loss of function have no effect? ( to read more about this).
  • Nice overview on Toll-like receptors & their therapeutic potential in Parkinson’s & other α-synucleinopathies. Could largeting TLRs be an effective therapeutic strategy to slow PD progression? ( to read more about this).
  • Interesting insights into some of the discussions at the recent Keystone Symposium meeting in Colorado (June, 2019). Prof Don Cleveland was discussing single gene transformation of astrocytes into dopamine neurons in mice (Wow! – to read more about this).
  • Very interesting review exploring “the relationship between important infectious pathogens & Parkinsonism, including symptoms of Parkinsonism following infectious etiologies, infectious contributions to neuroinflammation & neurodegenerative processes” ( to read more about this).
  • Nice overview on the link between the appendix & Parkinson’s risk ( to read more about this).

  • A useful assessment of severe constipation in Parkinson’s & in Parkinsonisms – covering its prevalence & affecting factors ( to read more about this).
  • It is a fair question: Can GBA-associated Parkinson’s be modeled in mice? Most current GBA-PD models are simply Gaucher models with a bit of PD thrown in ( to read more about this).
  • A useful review on the role of the endolysosomal system in Parkinson’s. The endolysosomal system is a highly dynamic series of membranous organelles specialized for regulating both intracellular trafficking & proteostasis ( to read more about this).
  • A useful systematic review of genetic variants associated with cognitive impairment & depressive symptoms in Parkinson’s (Click here to read more about this).
  • Where do we stand? Outstanding discussion on the outstanding questions (& questions outstanding) in our current understanding of mitophagy: the biological process of removing/recycling mitochondria, genes involved are intimately associated with Parkinson’s ( to read more about this).
  • A timely review of research on engineering the microbiome to improve drug outcomes or “Pharmacomicrobiomics” – includes the recent Parkinson’s/Ldopa research ( to read more about this).

  • An excellent overview of the current state of biotech efforts focused on small-molecule drugs & biologics that alter the microbiome (or its interaction with the host – to read more about this).
  • A uesful review of the research on dietary supplements in the management of Parkinson’s (everyone is here: NAC, Naicin, flavonoids, EGCG,… – to read more about this).
  • If I wanted to learn more about multiple system atrophy (MSA), I would start with this review ( to read more about this).
  • Researchers layout the research/arguments justifying a clinical trial of Cysteamine in Parkinson’s ( to read more about this).
  • An interesting new angle for neurodegenerative conditions: this perspective article outlines the mechanisms of how mitochondrial import & degrade proteins, & how these processes may be linked to Parkinson’s-associated a-synuclein & Alzheimer’s-associated β-amyloid (Click here to read more about this).
  • The emerging roles for high‐density lipoproteins in neurodegenerative conditions like Parkinson’s & Alzheimer’s ( to read more about this).
  • Researchers ask if artificial intelligence (AI) can solve “Eroom’s Law”. They explain how advances in AI can be used to reshape key steps of clinical trial design towards increasing trial success rates. This is fascinating! ( to read more about this).

  • Interesting review of mitophagy (removal of old mitochondria) in Parkinson’s – From pathogenesis to treatment ( to read more about this).
  • Could glycolipid changes over time be causing the proteinopathy in Parkinson’s? Researchers probe this idea in an interesting new review ( to read more about this).
  • An interesting review of how new discoveries about Parkinson’s-associated protein α-synuclein are impacting on our current understanding of the protein & the conditions, & where this information may direct the field ( to read more about this).
  • Researchers have published a review (and hypothesis) on how lipid interactions may play a role as trans-acting effectors in producing distinct strains of α-synuclein aggregates ( to read more about this).
  • Could Malassezia play a role in #Parkinsons? And if so, should we be evaluating antifungal drugs as a possible therapeutic intervention? (Click here to read more about this).

 

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

And there it is, just some of the highlights from July 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 August!


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.


3 comments

  1. Peter Cobbold

    Psoriasis, appendicitis, gut inflammation….increase risk of iPD. Could a common cause be peripheral cytokines accessing the brain and promoting an inappropriate pro-inflammatory response ?

    Like

    • Peter Cobbold

      Yes.
      But ergothioneine is missing.
      Otherwise all the ingredients of my personal cocktail are listed. I would myself put much more emphasis on D3. Several of the xenobiotics have poor biological availability with uncertain risk long term. I avoid them and take only physiological, endogenous agents. But I dont hold my breath expceting pharma to test a combination iif unpatentable agents. And trials with one agent at a time are near useless when feedback loops are considered. eg https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180583
      When such a “sytems biology” approach to PD is embraced we should start to see progress.

      Anyone contemplating taking all the antioxidants in that list needs to be aware that a degree of oxidative stress is important in the physiological control of blood pressure, and smooth and skeletal muscle function. ” Reductive stress” due tp overdoing antioxidants can have symptoms resembling those known for PD. Been there, done that.

      Like

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