No association of <i>GBA</i> mutations and multiple system atrophy

Srulijes, Karin; Hauser, Ann‐Kathrin; Guella, Ilaria; Asselta, Rosanna; Brockmann, Kathrin; Schulte, Claudia; Soldà, Giulia; Cilia, Roberto; Maetzler, Walter; Schöls, Ludger; Wenning, Gregor K.; Poewe, Werner; Barone, Paolo; Wüllner, U.; Oertel, Wolfgang H.; Berg, Daniela; Goldwurm, Stefano; Gasser, Thomas

doi:10.1111/ene.12086

Cited by 30 publications

(22 citation statements)

References 10 publications

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“…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.…”

Section: Discussionsupporting

confidence: 63%

“…In the remaining 135 cases, the clinical diagnosis was still uncertain and these patients are reported here as suffering from undefined primary parkinsonism (PKS). The majority of MSA cases ( N = 113) had been previously reported in a multicentre collaborative study on GBA involvement in MSA [10]. Patients with suspect of secondary parkinsonism were excluded.…”

Section: Methodsmentioning

confidence: 99%

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Glucocerebrosidase mutations in primary parkinsonism

Asselta

Rimoldi

Siri

et al. 2014

Parkinsonism & Related Disorders

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IntroductionMutations 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.MethodsWe studied 2766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2350 PD), and 1111 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.ResultsFour 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).ConclusionGBA 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.

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Section: Discussionsupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Glucocerebrosidase mutations in primary parkinsonism

Asselta

Rimoldi

Siri

et al. 2014

Parkinsonism & Related Disorders

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“…Most inclusions exhibited glucocerebrosidase immunofluorescence in the brains from GBA1-mutation carriers (Goker-Alpan et al, 2010), which suggests a pathophysiological link between mutant glucocerebrosidase expression and a-synuclein metabolism. Notably, GBA1 mutation status has no reported effect on multiple system atrophy (MSA), a progressive neurodegenerative disorder characterized by a-synuclein deposits in oligodendroglial cytoplasmic inclusions (Goker-Alpan et al, 2006;Segarane et al, 2009;Srulijes et al, 2013), which might imply different mechanisms for a-synuclein accumulation in neuronal and glial cells.…”

Section: Gaucher Mutations: a Common Genetic Risk For Synucleinopathiesmentioning

confidence: 99%

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Sardi¹,

Cheng²,

Shihabuddin³

2015

Progress in Neurobiology

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Gaucher disease, the most common lysosomal storage disease, is caused by a recessively inherited deficiency in glucocerebrosidase and subsequent accumulation of toxic lipid substrates. Heterozygous mutations in the lysosomal glucocerebrosidase gene (GBA1) have recently been recognized as the highest genetic risk factor for the development of α-synuclein aggregation disorders ("synucleinopathies"), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased glucocerebrosidase activity has been demonstrated to promote α-synuclein misprocessing. Furthermore, aberrant α-synuclein species have been reported to downregulate glucocerebrosidase activity, which further contributes to disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect glucocerebrosidase insufficiency with α-synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1-related synucleinopathies, and potentially, for non-GBA1-associated neurodegenerative diseases. In summary, the link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.

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“…The prevalence of GBA mutations among patients with MSA has been studied by a few groups in recent years, and has yielded varied results. [19][20][21][22][23][24][25] Six studies have found no association between GBA mutations and MSA.…”

Section: Glucocerebrosidase Genementioning

confidence: 99%

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

Sklerov¹,

Waters²

2016

US Neurology

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Multiple system atrophy (MSA) is a progressive, adult-onset, neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia, autonomic failure, and corticospinal tract dysfunction. It is considered a rare disease, similar in frequency to the more well-known neurodegenerative disease amyotrophic lateral sclerosis or Lou Gehrig’s disease. Though MSA has not traditionally been considered a genetic disease, new evidence is emerging supporting some genetic predisposition in many patients. In this short review, we will discuss advances in the knowledge of genetics in MSA and how this has furthered our understanding of the pathophysiology of the disease. There is still much unknown about this disease, but some of the recent advances made in MSA genetics may give important clues to understanding the pathogenesis and treatment of this disease.

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No association of GBA mutations and multiple system atrophy

Cited by 30 publications

References 10 publications

Glucocerebrosidase mutations in primary parkinsonism

Glucocerebrosidase mutations in primary parkinsonism

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Understanding Multiple System Atrophy—Could Genetics Lead the Way?

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