Is Parkinson's disease a vesicular dopamine storage disorder?: Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum

The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson’s disease (PD) is still unknown. Intraneuronally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [ 3H]dihydrotetrabenazine were profoundly reduced in PD by 87–90% and 71– 80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in P

Torpedoes in Parkinson's disease, Alzheimer's disease, essential tremor, and control brains

Purkinje cell axonal swellings ("torpedoes"), described in several cerebellar disorders as well as essential tremor (ET), have not been quantified in common neurodegenerative conditions

Systematic analysis of the gerontome reveals links between aging and age-related diseases

In model organisms, over 2,000 genes have been shown to modulate aging, the collection of which we call the ‘gerontome’. Although some individual aging-related genes have been the subject of intense scrutiny, their analysis as a whole has been limited. In particular, the genetic interaction of aging and age-related pathologies remain a subject of debate. In this work, we perform a systematic analysis of the gerontome across species, including human aging-related genes. First, by classifying aging-related genes as pro- or anti-longevity, we define distinct pathways and genes that modulate aging in different ways. Our subsequent comparison of aging-related genes with age-related disease genes reveals species-specific effects with strong overlaps between aging and age-related diseases in mice, yet surprisingly few overlaps in lower model organisms. We discover that genetic links between aging and age-related diseases are due to a small fraction of aging-related genes which also tend to have a high network connectivity. Other insights from our systematic analysis include assessing how using datasets with genes more or less studied than average may result in biases, showing that age-related disease genes have faster molecular evolution rates and predicting new aging-related drugs based on drug-gene interaction data. Overall, this is the largest systems-level analysis of the genetics of aging to date and the first to discriminate anti- and pro-longevity genes, revealing new insights on aging-related genes as a whole and their interactions with age-related diseases

Metabotropic glutamate receptor II in the brains of Parkinsonian patients

Abstract Modulation of basal ganglia group II metabotropic glutamate re

Participants’ perspectives of “NeuroSask: Active and Connect”—a virtual chronic disease management program for individuals with a neurological condition

IntroductionNeurological conditions account from more than half of Canadians requiring chronic care. Both physical activity and the development of a self-management skillset are critical components supporting individuals with chronic health conditions. “NeuroSask: Active and Connected” is a virtual chronic disease management program offering twice weekly neuro-physiotherapist directed “active” exercise sessions, followed by weekly knowledge-exchange “connect” sessions with invited guest experts. NeuroSask was launched April 2020 in response to the restricted services and supports for people with neurological conditions. The program aimed to provide seated physical activity, social interaction, and access to expertise in neurological conditions and neurorehabilitation. A program evaluation of NeuroSask was conducted to gain participants’ perspectives.MethodsAll participants registered for the NeuroSask program were invited to complete optional online surveys (SurveyMonkey) circulated by email at 3 occasions post-program launch: 10 weeks, 1 year, and 2 years. Participants could complete any one or all of the surveys, at their discretion. The number of potential respondents changed dependent on the total number of participants registered for NeuroSask at the time the survey was circulated. Questions were co-designed by multi-stakeholder team members. Descriptive statistics were used for closed-ended questions and a reflexive thematic analysis was completed with coding conducted in NVivo 12 Plus for open-ended text.ResultsResponse rates (participants/registrants) were as follows: 10-week survey 260/793, one year survey 326/1224, and 2-year survey 434/1989. 90% of participants reported being in either the age categories of 40–59 years or above 60 years. 75% of both survey respondents and program registrants were female. 70% of both survey respondents and program registrants reported a diagnosis of multiple sclerosis and 30% reported other neurological conditions. Survey respondents were from all ten Canadian provinces, with 45% reporting living outside of large cities. Respondents reported preferring online vs. in person format for this type of programming. Three main themes, and eight corresponding subthemes were identified highlighting the perceived impact and key components of the NeuroSask program: Theme 1 “together in a positive and encouraging environment” (subthemes 1a: connection, 1b: empowerment); Theme 2 “access to enthusiastic qualified leaders from home” (subthemes 2a: leader characteristics, 2b: accessibility, 2c: program logistics); Theme 3 “being able to enjoy everyday life” (subthemes 3a: symptom benefits and beyond, 3b: carry-over, 3c: keep going, please do not cancel).ConclusionNeuroSask is an example of an accessible and meaningful virtual approach to providing ongoing support for some individuals with neurological conditions. It was perceived as beneficial for fostering community and connection in a positive environment with perceived benefits extending beyond symptom management to participant reported improvements in function, daily life, and disease experience

Cisplatin Ototoxicity in Children

Cisplatin is a highly effective chemotherapy medicine used in the treatment of many childhood cancers. Like all medications, cisplatin has many side effects and as always the treatment of cancer in children is a balance between the risks of the medications used and their potential benefits. While many side effects of cisplatin chemotherapy are reversible, one major side effect is permanent and irreversible hearing loss (ototoxicity) in both ears which may worsen with time. The severity of cisplatin-related ototoxicity is associated with age and the cumulative dose received: the younger the child and the higher the total dose, the more severe the hearing loss may be. The spectrum of hearing loss varies from mild to moderate high tone hearing loss, to profound loss across the hearing range and permanent deafness. In addition to hearing loss, some children, especially adolescents, also experience tinnitus and vertigo. Cisplatin ototoxicity is one of most important of the many long-term effects experienced by children who are cured of their cancer. The burden of this toxicity may be compounded by other long-term health issues that emerge with time. This chapter will focus on cisplatin-induced hearing loss, its mechanisms, its health impact on the young person and ways to mitigate or reduce the severity of ototoxicity. This chapter has been written by a multi-disciplinary team including paediatric oncologists, audiologists, a psychologist, a health scientist and a parent of a child growing up with high frequency hearing loss

Clinical Conditions “Suggestive of Progressive Supranuclear Palsy”—Diagnostic Performance

Background: The Movement Disorder Society diagnostic criteria for progressive supranuclear palsy introduced the diagnostic certainty level “suggestive of progressive supranuclear palsy” for clinical conditions with subtle signs, suggestive of the disease. This category aims at the early identification of patients, in whom the diagnosis may be confirmed as the disease evolves. Objective: To assess the diagnostic performance of the defined clinical conditions suggestive of progressive supranuclear palsy in an autopsy-confirmed cohort. Methods: Diagnostic performance of the criteria was analyzed based on retrospective clinical data of 204 autopsy-confirmed patients with progressive supranuclear palsy and 216 patients with other neurological diseases. Results: The conditions suggestive of progressive supranuclear palsy strongly increased the sensitivity compared to the National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria. Within the first year after symptom onset, 40% of patients with definite progressive supranuclear palsy fulfilled criteria for suggestive of progressive supranuclear palsy. Two-thirds of patients suggestive of progressive supranuclear palsy evolved into probable progressive supranuclear palsy after an average of 3.6 years. Application of the criteria for suggestive of progressive supranuclear palsy reduced the average time to diagnosis from 3.8 to 2.2 years. Conclusions: Clinical conditions suggestive of progressive supranuclear palsy allow earlier identification of patients likely to evolve into clinically possible or probable progressive supranuclear and to have underlying progressive supranuclear palsy pathology. Further work needs to establish the specificity and positive predictive value of this category in real-life clinical settings, and to develop specific biomarkers that enhance their diagnostic accuracy in early disease stages

Mitochondrial DNA heteroplasmy distinguishes disease manifestation in PINK1/PRKN-linked Parkinson’s disease

Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA (mtDNA) integrity and inflammation as disease modifiers in carriers of mutations in these genes. MtDNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load (AUC = 0.83, CI:0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbor more heteroplasmic mtDNA variants in blood (p = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in iPSC-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and postmortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Lastly, the heteroplasmic mtDNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, p = 0.0074). PINK1/PRKN mutations predispose individuals to mtDNA variant accumulation in a dose- and disease-dependent manner

Enhanced production of multi-strange hadrons in high-multiplicity proton-proton collisions

At sufficiently high temperature and energy density, nuclear matter undergoes a transition to a phase in which quarks and gluons are not confined: the quark-gluon plasma (QGP)(1). Such an exotic state of strongly interacting quantum chromodynamics matter is produced in the laboratory in heavy nuclei high-energy collisions, where an enhanced production of strange hadrons is observed(2-6). Strangeness enhancement, originally proposed as a signature of QGP formation in nuclear collisions(7), is more pronounced for multi-strange baryons. Several effects typical of heavy-ion phenomenology have been observed in high-multiplicity proton-proton (pp) collisions(8,9), but the enhanced production of multi-strange particles has not been reported so far. Here we present the first observation of strangeness enhancement in high-multiplicity proton-proton collisions. We find that the integrated yields of strange and multi-strange particles, relative to pions, increases significantly with the event charged-particle multiplicity. The measurements are in remarkable agreement with the p-Pb collision results(10,11), indicating that the phenomenon is related to the final system created in the collision. In high-multiplicity events strangeness production reaches values similar to those observed in Pb-Pb collisions, where a QGP is formed.Peer reviewe