Advances in the genetics of Parkinson disease. Nature reviews

Nature Reviews Neurology (Impact Factor: 15.36). 07/2013; DOI: 10.1038/nrneurol.2013.132


Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the
result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next‑generation sequencing studies of familial parkinsonism, as well as candidate gene and genome‑wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome‑mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease‑modifying therapies.

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Available from: Joanne Trinh, Oct 10, 2015
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    • "In recent years, linkage analyses in large families and the positional cloning of an increasing number of genes that cause monogenic forms of PD have provided new insight into the pathogenesis of this disorder. To date, mutations in >18 genes have implicated as a cause of familial PD or levodoparesponsive parkinsonism (e.g., SNCA, LRRK2, VPS35) (Trinh and Farrer, 2013). "
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    ABSTRACT: Funayama et al. recently identified mutations in the CHCHD2 gene in Japanese families with autosomal dominant Parkinson's disease, increasing our knowledge about the monogenic cause of this disorder. However, there is no report regarding the association between CHCHD2 and Parkinson's disease (PD) in the Chinese Han population. The aim of this study was to obtain the prevalence of CHCHD2 mutations in Chinese familial PD. Genetic analysis of mutations in CHCHD2 gene was conducted in a cohort of 92 families with autosomal dominant Parkinson's disease from mainland China. No mutations in CHCHD2 gene were identified, suggesting that CHCHD2 mutations might not be a common cause of PD in Chinese familial cases.
    Neurobiology of aging 09/2015; DOI:10.1016/j.neurobiolaging.2015.08.010 · 5.01 Impact Factor
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    • "The failure of normal cellular processes that occur in relation to the aging process are also believed to contribute to the increased vulnerability of DA neurons (Schapira and Jenner, 2011; Rodriguez et al., 2014). While the familial forms of PD, that have been described, involve mutations in a number of genes (Kieburtz and Wunderle, 2013; Trinh and Farrer, 2013), mitochondrial dysfunction, neuroinflammation and environmental factors are increasingly appreciated as key determinants of dopaminergic neuronal susceptibility in PD, and are a feature of both familial and sporadic forms of the disease (Ryan et al., 2015). In both cases, oxidative stress is thought to be the common underlying mechanism that leads to cellular dysfunction and, eventual cell death. "
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    ABSTRACT: Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
    Frontiers in Neuroanatomy 07/2015; 9(91). DOI:10.3389/fnana.2015.00091 · 3.54 Impact Factor
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    • "Indeed, even severe primary mitochondrial diseases caused by loss-of-function nuclear or mitochondrial DNA mutations affecting mitochondrial electron transport chain complexes exhibit variable cardiac involvement (Holmgren et al, 2003). Furthermore, the heart is generally spared in human genetic diseases primarily impacting either the mitophagy mitochondrial quality control pathway (e.g., Parkinson's disease) or the mitochondrial dynamics apparatus (e.g., Charcot–Marie– Tooth syndrome and dominant optic atrophy) (Trinh & Farrer, 2013; Bombelli et al, 2014). Progressive neurological degeneration, and not heart disease, is the most common heritable feature in genetic disorders affecting mitophagy signaling and mitochondrial dynamism. "
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    ABSTRACT: Mitochondria of adult cardiomyocytes appear hypo-dynamic, lacking interconnected reticular networks and the continual fission and fusion observed in many other cell types. Nevertheless, proteins essential to mitochondrial network remodeling are abundant in adult hearts. Recent findings from cardiac-specific ablation of mitochondrial fission and fusion protein genes have revealed unexpected roles for mitochondrial dynamics factors in mitophagic mitochondrial quality control. This overview examines the clinical and experimental evidence for and against a meaningful role for the mitochondrial dynamism-quality control interactome in normal and diseased hearts. Newly discovered functions of mitochondrial dynamics factors in maintaining optimal cardiac mitochondrial fitness suggest that deep interrogation of clinical cardiomyopathy is likely to reveal genetic variants that cause or modify cardiac disease through their effects on mitochondrial fission, fusion, and mitophagy. © 2015 The Author. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 04/2015; 7(7). DOI:10.15252/emmm.201404575 · 8.67 Impact Factor
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