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.

8 Reads
  • Source
    • "These discoveries were followed by population-based genome-wide association studies (GWAS) that identified an additional 20 PD risk loci. Houlden and Singleton [7] recently summarized the genetic, clinical, and pathological findings of autosomal dominant and recessive mutations and discussed the discovery of genetic risk loci for PD with an emphasis on LRRK2 and GBA (glucocerebrosidase). Indeed 5e10% of PD patients have GBA mutations, numerically making this the most important risk factor for the disease [8]. Even though this might represent a small percentage of PD cases, genetic studies are invaluable to elucidate the pathways contributing to clinical diagnosis and most importantly to identify populations at risk. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. PD is a complex syndrome with different clinical subtypes and a wide variability in disorder course. In order to deliver better clinical management of PD patients and discovery of novel therapies, there is an urgent need to find sensitive, specific, and reliable biomarkers. The development of biomarkers will not only help the scientific community to identify populations at risk, but also facilitate clinical diagnosis. Furthermore, these tools could monitor progression, which could ultimately deliver personalized therapeutic strategies. The field of biomarker discovery in PD has attracted significant attention and there have been numerous contributions in recent years. Although none of the parameters have been validated for clinical practice, some candidates hold promise. This review summarizes recent advances in the development of PD biomarkers and discusses new strategies for their utilization.
    Parkinsonism & Related Disorders 09/2015; 22 Suppl 1. DOI:10.1016/j.parkreldis.2015.09.048 · 3.97 Impact Factor
    • "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 "
    [Show abstract] [Hide abstract]
    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
  • Source
    • ", 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 . "
    [Show abstract] [Hide abstract]
    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
Show more