The genetics and neuropathology of Parkinson's disease

Molecular Neuroscience Department, UCL Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, Queen Square, London, UK.
Acta Neuropathologica (Impact Factor: 10.76). 07/2012; 124(3):325-38. DOI: 10.1007/s00401-012-1013-5
Source: PubMed


There has been tremendous progress toward understanding the genetic basis of Parkinson's disease and related movement disorders. We summarize the genetic, clinical and pathological findings of autosomal dominant disease linked to mutations in SNCA, LRRK2, ATXN2, ATXN3, MAPT, GCH1, DCTN1 and VPS35. We then discuss the identification of mutations in PARK2, PARK7, PINK1, ATP13A2, FBXO7, PANK2 and PLA2G6 genes. In particular we discuss the clinical and pathological characterization of these forms of disease, where neuropathology has been important in the likely coalescence of pathways highly relevant to typical PD. In addition to the identification of the causes of monogenic forms of PD, significant progress has been made in defining genetic risk loci for PD; we discuss these here, including both risk variants at LRRK2 and GBA, in addition to discussing the results of recent genome-wide association studies and their implications for PD. Finally, we discuss the likely path of genetic discovery in PD over the coming period and the implications of these findings from a clinical and etiological perspective.

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    • "Nevertheless, 16.9% decrease in total sleep was reported. Neuropathologically, a widespread and non-specific nigral degeneration and Lewy body deposits were reported [117] Gluco-cerebrosidase (GBA)-associated PD "
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    ABSTRACT: Parkinson disease is one of the neurodegenerative diseases that benefited the most from the use of non-human models. Consequently, significant advances have been made in the symptomatic treatments of the motor aspects of the disease. Unfortunately, this translational success has been tempered by the recognition of the debilitating aspect of multiple non-motor symptoms of the illness. Alterations of the sleep/wakefulness behavior experienced as insomnia, excessive daytime sleepiness, sleep/wake cycle fragmentation and REM sleep behavior disorder are among the non-motor symptoms that predate motor alterations and inevitably worsen over disease progression. The absence of adequate humanized animal models with the perfect phenocopy of these sleep alterations contribute undoubtedly to the lack of efficient therapies for these non-motor complications. In the context of developing efficient translational therapies, we provide an overview of the strengths and limitations of the various currently available models to replicate sleep alterations of Parkinson's disease. Our investigation reveals that although these models replicate dopaminergic deficiency and related parkinsonism, they rarely display a combination of sleep fragmentation and excessive daytime sleepiness and never REM sleep behavior disorder. In this light, we critically discuss the construct, face and predictive validities of both rodent and non-human primate animals to model the main sleep abnormalities experienced by patients with PD. We conclude by highlighting the need of integrating a network-based perspective in our modeling approach of such complex syndrome in order to celebrate valid translational models. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Sleep Medicine Reviews 02/2015; DOI:10.1016/j.smrv.2015.02.005 · 8.51 Impact Factor
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    • ", 2013 ) . Additionally , it has been reviewed that A53T , A30P , and E46K mutations in general have a neuropathology of nigral neuronal loss and LB pathology in cortical and brainstem while multiplication mutations having temporal lobe vacuolation in addition to LB pathology ( Houlden and Singleton , 2012 ) . Furthermore , more neuropathological fea - tures have been demonstrated in subsequent researches with hu - man and animal models carrying SNCA single mutations ( Cannon et al . "
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    ABSTRACT: The groundbreaking discovery of mutations in the SNCA gene in a rare familial form of Parkinson's disease (PD) has revolutionized our basic understanding of the etiology of PD and other related disorders. Genome-wide Association Studies has demonstrated a wide array of single-nucleotide polymorphisms associated with the increasing risk of developing the more common type, sporadic PD, further corroborating the genetic etiology of PD. Among them, SNCA is a gene responsible for encoding α-synuclein, a protein found to be the major component of Lewy body and Lewy neurite, both of these components are the pathognomonic hallmarks of PD. Thus, it has been postulated that this gene plays specific roles in pathogenesis of PD. Here, we summarize the basic biological characteristics of the wild type of the protein (wt-α-synuclein) as well as genetic and epigenetic features of its encoding gene (SNCA) in PD. Based on these characteristics, SNCA may be involved in PD pathogenesis in at least 2 ways: wt-α-synuclein overexpression and its mutation types via different mechanisms. Associations between SNCA mutations and other Lewy body disorders, such as dementia with Lewy bodies and multiple system atrophy, are also mentioned. Finally, it is necessary to explore the influences which SNCA exerts on clinical and neuropathological phenotypes by promoting the transfer of scientific research into practice, such as clinical evaluation, diagnosis, and treatment of the disease. We believe it is promising to target SNCA for developing novel therapeutic strategies for parkinsonism. Copyright © 2014 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.10.042 · 5.01 Impact Factor
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    • "Neuropathological, biochemical and genetic evidences (Spillantini et al., 1998, 1997; Vekrellis et al., 2011) have supported the implication of alpha-synuclein as the cause of these diseases. More specifically, mutations, duplications and triplications of the alpha-synuclein gene (SNCA) locus are causes of familial forms of PD and DLB (Houlden and Singleton, 2012) and SNCA has also been identified as a risk factor in all the PD genome wide association studies (Singleton et al., 2013). Additionally, alpha-synuclein deposits can be found with other proteinaceous aggregates (Tau, A␤, prions, etc.) characteristics of other neurodegenerative diseases (Arima et al., 1998; Charles et al., 2000; Doherty et al., 2004; Forman et al., 2002; Haïk et al., 2002; Lippa et al., 1999; Spillantini et al., 1998; Takeda et al., 1998; Wakabayashi et al., 2000). "
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    ABSTRACT: Parkinson's disease is one of several neurodegenerative diseases associated with a misfolded, aggregated and pathological protein. In Parkinson's disease this protein is alpha-synuclein and its neuronal deposits in the form of Lewy bodies are considered a hallmark of the disease. In this review we describe the clinical and experimental data that have led to think of alpha-synuclein as a prion-like protein and we summarize data from in vitro, cellular and animal models supporting this view.
    Virus Research 11/2014; 42. DOI:10.1016/j.virusres.2014.10.016 · 2.32 Impact Factor
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