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Glucocerebrosidase mutations in 108 neuropathologically confirmed cases of multiple system atrophy

Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square, UK WC1N 3BG.
Neurology (Impact Factor: 8.3). 04/2009; 72(13):1185-6. DOI: 10.1212/01.wnl.0000345356.40399.eb
Source: PubMed
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    • "Furthermore it may be interesting to evaluate GBA mutation frequency within the LBD spectrum. GBA mutations do not seem to play a role in the predisposition both to MSA, as previously evidenced by us [10] and others [9], and to tauopathies. This may underlie a different involvement of the GBA-mediated lysosomal impairment in different forms of parkinsonism . "
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    ABSTRACT: Introduction Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson’s Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism. Methods We studied 2,766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2,350 PD), and 1,111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P. Results Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR=7.2, CI=3.3-15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR= 21.9, CI=6.8-70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52±10 vs. 57±10 years, P<0.0001) and were more likely to have a positive family history of PD (34% vs. 20%, P<0.001). Conclusion GBA dysfunction is relevant for synucleinopathies, such as PD and DLB, except for MSA, in which pathology involves oligodendrocytes, and the tauopathies PSP and CBD. The risk of developing DLB is three-fold higher than PD, suggesting a more aggressive phenotype.
    Parkinsonism & Related Disorders 09/2014; 20(11). DOI:10.1016/j.parkreldis.2014.09.003 · 4.13 Impact Factor
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    • "GBA1 mutations have been found in 7% patients with idiopathic PD, and up to 30% of Ashkenazi Jewish patients, with only 1.3% in the general population (Sidransky and Lopez, 2012; Sidransky et al., 2009). Mutations in GBA1 have also been reported in DLB but not MSA (Farrer et al., 2009; Segarane et al., 2009), supporting the difference in mechanism between MSA and Lewy related pathology. GBA1 mutations presumably increase susceptibility to PD by blocking the lysosomal degradation of a-synuclein (Manning- Bo g et al., 2009), but it has been difficult to understand how a modest reduction in enzyme activity could impair lysosomal function enough to produce a degenerative disorder. "
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    ABSTRACT: Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson's disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. In this article, we review the role of synuclein at the nerve terminal and in membrane remodeling. We also consider the prion-like propagation of misfolded synuclein as a mechanism for the spread of degeneration through the neuraxis.
    Neuron 09/2013; 79(6):1044-66. DOI:10.1016/j.neuron.2013.09.004 · 15.98 Impact Factor
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    • "The loss of positive charge in R262G is likely to affect the interactions of the protein with other molecules. Another amino acid change in the same position, R262H, has been linked to PD by the Leiden Open Variant Database [11] and has been found in multiple system atrophy [3] but was not previously found in GD. Related to V447E the mutant amino acid was predicted to alter the β-sheet secondary structure found in that region. "
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    ABSTRACT: To determine the frequency of mutations responsible for Gaucher's disease, we systematically sequenced the GBA1 gene as part of a molecular characterization of 73 adult patients in the United Kingdom. Five hitherto unknown pathogenic variants were identified, one of which is a splice site change; the others are novel missense mutations. Given that GBA1 gene mutations are an important risk factor for the development of Parkinson's disease, we contend that a complete analysis and molecular characterization of both the known and novel GBA1 variants will be needed before the biochemical processes underlying this genetic association can be fully understood.
    Molecular Genetics and Metabolism 05/2012; 106(4):495-7. DOI:10.1016/j.ymgme.2012.05.006 · 2.83 Impact Factor
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