Parkinson's disease (PD), a progressive neurodegenerative disorder, has long been associated with mitochondrial dysfunction in both sporadic and familial forms of the disease. Mitochondria are ...crucial for maintaining cellular homeostasis, and their dysfunction is detrimental to dopaminergic neurons. These neurons are highly dependent on mitochondrial adenosine triphosphate (ATP) and degenerate in PD. Mitochondria contain their own genomes (mtDNA). The role of mtDNA has been investigated in PD on the premise that it encodes vital components of the ATP-generating oxidative phosphorylation (OXPHOS) complexes and accumulates somatic variation with age. However, the association between mtDNA variation and PD remains controversial. Herein, we provide an overview of previously published studies on the role of inherited as well as somatic (acquired) mtDNA changes in PD including point mutations, deletions and depletion. We outline limitations of previous investigations and the difficulties associated with studying mtDNA, which have left its role unresolved in the context of PD. Lastly, we highlight the potential for further research in this field and provide suggestions for future studies. Overall, the mitochondrial genome is indispensable for proper cellular function and its contribution to PD requires further, more extensive investigation.
•Studies investigating mtDNA variation in PD have produced conflicting results.•This may be due, in part, to methodological inconsistencies between studies.•Studies should consider more standardised approaches to study mtDNA variation in PD.•Nuclear genes and mitochondrial copy number should be considered in future studies.•Mitochondrial-derived peptides should also be further investigated.
Objective
The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of ...individual‐level genetic data available.
Methods
We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome‐wide association study meta‐analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene‐based analyses and functional enrichment analyses.
Results
A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error SE = 0.022, p = 0.013). Although no single locus reached genome‐wide significance, MAGMA gene‐based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow‐sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.
Interpretation
The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high‐risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278
The aggregation of misfolded proteins has long been regarded as a pathological event in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. However, ...the exact molecular mechanisms that govern protein metabolism that may lead to toxicity remain largely unclear. Originally targeted as the causative agent, it has since become evident that aggregation formation may not be necessary for disease progression and studies show that they may even serve functional and protective roles. Although the focus has since shifted to the toxicity of intermediate protein species preceding aggregation formation, many questions remain: Is the blame for the neural destruction to be put on one event alone, or rather on a state of cellular disequilibrium resulting from multiple events? If the cause is multifactorial, then what triggers the toxic cascade and how can this be targeted therapeutically? In order to understand the origin of toxicity, the exact underlying mechanism and impact of each contributing process must be assessed. Therefore, the structural properties, mechanism of formation, cytotoxic and/or protective effects, as well as the clinical impact of protein intermediates and aggregates will be reviewed here with the goal to establish a neurodegenerative disease model aimed at improving current therapeutics, which may ultimately contribute towards improved treatment modalities.
•Many different proteins are involved in aggregation formation.•Amyloid formation is, to a certain extent, physiological.•Protein aggregation can be protective against cell death.•Loss of cellular equilibrium leads to multisystem failures.•Disruption of homeostasis underlies neuronal degeneration.
G2019S in
LRRK2
is the most common mutation associated with Parkinson’s disease (PD). Highest frequencies are in North African Arabic (30–41%) and Ashkenazi Jewish (6–30%) populations, mostly due to ...founder effects. Here, we investigated the frequency of G2019S in 647 unrelated South African PD patients from different ancestral origins. It was found in only 1.2% (8/647) of patients. Notably, none of the 91 individuals of African ancestry had G2019S. It was present in 1.9% (3/154) and 1% (5/493) of early- and late-onset cases, respectively. The frequency of G2019S exhibits ethnic-specific differences and warrants further study in sub-Saharan African populations.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disorder characterized by progressive degeneration of right ventricular myocardium, arrhythmias and an increased risk of sudden ...death at a young age. By linkage analysis, ARVC type 6 was previously mapped to a 10.6 cM region on chromosome 10p12-p14 in a large North American kindred. To date, the genetic defect that causes ARVC6 has not been identified.
We identified a South African family of 13 members with ARVC segregating as an autosomal dominant disorder. The diagnosis of ARVC was based on international diagnostic criteria. All available family members were genotyped with microsatellite markers at six known ARVC loci, and positional candidate gene screening was performed.
Genetic linkage and haplotype analysis provided lod scores that are highly suggestive of linkage to the ARVC6 locus on chromosome 10p12-p14, and the narrowing of the critical region to approximately 2.9 Mb. Two positional candidate genes (ITG8 and FRMD4A) were screened in which defects could possibly disrupt cell-cell adhesion. A non-positional candidate gene with apoptosis inducing properties, LAMR1P6 (laminin receptor 1 pseudogene 6) was also screened. Direct sequencing of DNA from affected individuals failed to detect disease-causing mutations in the exonic sequences of the three genes investigated.
The narrowing of the ARVC6 critical region may facilitate progress towards the identification of the gene that is involved in ARVC. Identification of the causative genes for ARVC will contribute to the understanding of the pathogenesis and management of this poorly understood condition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Parkinson's disease (PD) affects 1–2% of individuals above 60 years amounting to over 7 million people worldwide. Thus, PD has become an important contributor to the neurological disease burden. ...Nigeria is the most populous country in Africa, and alarmingly, approximately 5.25 million Nigerians are above 65 years and are therefore at risk for developing PD. We carried out a critical review of published literature on PD in Nigeria to summarize the findings and to evaluate gaps in knowledge. Seven electronic databases were searched for studies published in English before 18th July 2018. Search terms were ”Parkinson's disease” OR “Parkinson disease” OR “parkinsonian disorders” OR “Parkinsonism” AND “Nigeria”. A total of 44 articles (including eight reviews) published since 1969 were identified and reviewed. Amongst the original research articles, most (23) were on PD symptoms or prevalence. There were only two studies on genetics and two on environmental factors. The estimated crude prevalence of PD in Nigeria was lower (10–249/100 000) compared to studies published in Europe (65.6–12 500/100 000). Our findings suggest that PD is under-diagnosed in Nigeria. Possible environmental risk factors identified include blacksmithing and well-water contaminated with trace metals. Given the rising numbers of the ageing population in Nigeria, more studies to evaluate the prevalence and causes of PD in this country are urgently needed. To this end, more funding, resources and a workforce of well-trained neurologists and scientists are essential to manage the impending health burden of PD and related disorders in this country.
•To date, a total of 44 studies have been published on PD in Nigerian patients.•The estimated crude prevalence of PD in Nigeria was low (10–249/100 000).•Possible environmental risk factors are contaminated well-water and blacksmithing.•Only 2 genetic studies have been published on Nigerian PD patients.•More studies on the prevalence and causes of PD in Nigeria are urgently needed.
There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing ...offered for PD as the first step of our gene curation.
The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally.
We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial.
There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD.
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