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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    • "Excessive accumulation of aberrant proteins in the dopaminergic neurons cytoplasm may be caused by dysfunction of normal ALP pathway, which could ultimately results in cell death and the clinical manifestations of PD. And lysosomal enzymes including proteins encoded by GBA and SMPD1 play an important role in maintaining the ALP pathway normal functions [12] [13] "
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    ABSTRACT: Purpose: The protein encoded by sphingomyelin phosphodiesterase 1, acid lysosomal (SMPD1) is a lysosomal acid sphingomyelinase. While there are increasing evidences to suggest that lysosomal enzyme defects and Parkinson’s disease (PD) have strong associations, and recently, SMPD1 p.L302P (c.T911C, NM_000543) was found to be a risk factor for PD in Ashkenazi Jewish ancestry population, we try to investigate the possible association between SMPD1 p.L302P and sporadic PD in ethnic Chinese population. Methods: 455 sporadic PD and 476 health controls were included in our study. SMPD1 p.L302P (c.T911C) was genotyped by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and the results were confirmed by Sanger sequencing. Results: Our results showed that none of 455 sporadic PD and 476 health controls carried p.L302P. All of the 931 subjects’ genotypes were wild type TT. Our data indicated that in an ethnic Chinese population, p.L302P did not appear to be enriched in sporadic PD, and p.L302P may not be a risk factor for Chinese sporadic PD. And combine our data with the results from previous studies, we found that all of the 2,268 participants of Chinese population carrying no p.L302P. Conclusions: We could make a conclusion that p.L302P may not be common events for Chinese population. Sequencing of SMPD1 gene to find additional novel rare variants in the SMPD1 gene in diverse populations is needed.
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    • "The proportion of monogenic cases varies from 10% to 15% in different populations [4]. Intensive studies carried out over the past 15 years have revealed the involvement of a large number of different loci and genes in the development of PD [5]. "
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    ABSTRACT: Parkinson's disease (PD) is a widespread neurodegenerative disorder. Despite the intensive studies of this pathology, in general, the picture of the etiopathogenesis has still not been clarified fully. To understand better the mechanisms underlying the pathogenesis of PD, we analyzed the expression of 10 genes in the peripheral blood of treated and untreated patients with PD. 35 untreated patients with PD and 12 treated patients with Parkinson's disease (Hoehn and Yahr scores 1-2) were studied. An analysis of the mRNA levels of ATP13A2, PARK2, PARK7, PINK1, LRRK2, SNCA, ALDH1A1, PDHB, PPARGC1A, and ZNF746 genes in the peripheral blood of patients was carried out using reverse transcription followed by real-time PCR. A statistically significant and specific increase by more than 1.5-fold in the expression of the ATP13A2, PARK7, and ZNF746 genes was observed in patients with PD. Based on these results, it can be suggested that the upregulation of the mRNA levels of ATP13A2, PARK7, and ZNF746 in untreated patients in the earliest clinical stages can also be observed in the preclinical stages of PD, and that these genes can be considered as potential biomarkers of the preclinical stage of PD.
    Parkinson's Disease 10/2015; 2015(3):294396. DOI:10.1155/2015/294396 · 2.01 Impact Factor
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    • "Genetic findings over the last 25 years have altered our perception of what parkinsonism is; this was driven mostly by classical linkage methods in large familial aggregates with Mendelian patterns of disease inheritance [1]. Although for the most part these genetic variants account for a very small proportion of patients, they have provided crucial insights into the underlying pathophysiology of Parkinsonian disorders. "
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    ABSTRACT: Parkinsonism is an umbrella term for a group of disorders characterized by the clinical signs of tremor, bradykinesia, rigidity, and postural instability. On neuropathologic examination parkinsonism can display alternate protein pathologies (e.g. α-synucleinopathy or tauopathy) but the degeneration of nigral neurons is consistent. The main forms of parkinsonism are, Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Genetic studies from candidate gene, to unbiased genome-wide approaches including association and next-generation sequencing have nominated a number of disease determinants. Within this review we will highlight the genetic loci that are associated with disease and discuss the implications and importance for a better understanding of the genes involved and thus the underlying pathophysiology of these disorders.
    Parkinsonism & Related Disorders 09/2015; DOI:10.1016/j.parkreldis.2015.09.011 · 3.97 Impact Factor
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