Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

Sidransky, Ellen; Nalls, Michael A.; Aasly, Jan; Aharon‐Peretz, Judith; Annesi, Grazia; Barbosa, Egberto Reis; Bar‐Shira, Anat; Berg, Daniela; Brás, José; Brice, Alexis; Chen, Chiung‐Mei; Clark, Lorraine N.; Condroyer, Christel; Marco, Elvira Valeria De; Dürr, Alexandra; Eblan, Michael J.; Fahn, Stanley; Farrer, Matthew J.; Fung, Hon-Chung; Gan‐Or, Ziv; Gasser, Thomas; Gershoni‐Baruch, Ruth; Giladi, Nir; Griffith, Alida; Gurevich, Tanya; Januário, Cristina; Kropp, Peter; Lang, Anthony E.; Lee‐Chen, Guey‐Jen; Lesage, Suzanne; Marder, Karen; Mata, Ignacio; Mirelman, Anat; Mitsui, Jun; Mizuta, Ikuko; Nicoletti, Giuseppe; Oliveira, Catarina R.; Ottman, Ruth; Orr-Urtreger, Avi; Pereira, Lygia V.; Quattrone, Aldo; Rogaeva, Ekaterina; Rolfs, Arndt; Rosenbaum, Hanna; Rozenberg, Roberto; Samii, Ali; Samaddar, Ted; Schulte, Claudia; Sharma, Manu; Singleton, Andrew B.; Spitz, Mariana; Tan, Eng‐King; Tayebi, Nahid; Toda, Tatsushi; Troiano, André R.; Tsuji, Shoji; Wittstock, Matthias; Wolfsberg, Tyra G.; Wu, Yih‐Ru; Zabetian, Cyrus P.; Zhao, Yongxiang; Ziegler, Shira G.

doi:10.1056/nejmoa0901281

Cited by 1,862 publications

(1,746 citation statements)

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“…Also, as the vast organomegaly observed in patients with GD cannot be accounted for by the amount of GluCer storage alone, inflammation likely contributes to hepatic and splenic size. The observed failure of fusion of autophagosomes with lysosomes may also be relevant to the recently appreciated association between GD and parkinsonism (Sidransky et al ., 2009; Siebert et al ., 2014). In fact, there is literature suggesting that impaired autophagy and lysosomal dysfunction in neurodegenerative disorders can result in a failure to clear accumulated protein aggregates (Lynch‐Day et al ., 2012; Nixon, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, studying the link between lysosomal dysfunction and inflammation in GD may directly impact our understanding of a common neurodegenerative disorder of aging, Parkinson disease (PD). Mutations in the glucocerebrosidase gene ( GBA1) are an important genetic risk factor for PD and related Lewy body disorders (Sidransky et al ., 2009). A better understanding of the implications of lysosomal impairment and autophagy in GD may yield insights relevant to PD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

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SummaryGaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

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“…Homozygous GBA mutations cause Gaucher disease (GD), the most common lysosomal disorder, whereas heterozygous GBA mutations are the most common genetic risk factor for Parkinson disease (PD), present in 7–20% of all PD cases [1]. Compared to PD patients lacking GBA mutations (Non-GBA-PD), patients with heterozygous GBA mutations (GBA-PD) have an earlier age at onset, greater cognitive decline, and a faster rate of disease progression [2,3].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

et al. 2018

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Heterozygous mutations in GBA, the gene encoding the lysosomal enzyme glucosylceramidase beta/β-glucocerebrosidase, comprise the most common genetic risk factor for Parkinson disease (PD), but the mechanisms underlying this association remain unclear. Here, we show that in GbaL444P/WT knockin mice, the L444P heterozygous Gba mutation triggers mitochondrial dysfunction by inhibiting autophagy and mitochondrial priming, two steps critical for the selective removal of dysfunctional mitochondria by autophagy, a process known as mitophagy. In SHSY-5Y neuroblastoma cells, the overexpression of L444P GBA impeded mitochondrial priming and autophagy induction when endogenous lysosomal GBA activity remained intact. By contrast, genetic depletion of GBA inhibited lysosomal clearance of autophagic cargo. The link between heterozygous GBA mutations and impaired mitophagy was corroborated in postmortem brain tissue from PD patients carrying heterozygous GBA mutations, where we found increased mitochondrial content, mitochondria oxidative stress and impaired autophagy. Our findings thus suggest a mechanistic basis for mitochondrial dysfunction associated with GBA heterozygous mutations.Abbreviations: AMBRA1: autophagy/beclin 1 regulator 1; BECN1: beclin 1, autophagy related; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chloroyphenylhydrazone; CYCS: cytochrome c, somatic; DNM1L/DRP1: dynamin 1-like; ER: endoplasmic reticulum; GBA: glucosylceramidase beta; GBA-PD: Parkinson disease with heterozygous GBA mutations; GD: Gaucher disease; GFP: green fluorescent protein; LC3B: microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated form of microtubule-associated protein 1 light chain 3 beta; MitoGreen: MitoTracker Green; MitoRed: MitoTracker Red; MMP: mitochondrial membrane potential; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH transcription factor; NBR1: NBR1, autophagy cargo receptor; Non-GBA-PD: Parkinson disease without GBA mutations; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; RFP: red fluorescent protein; ROS: reactive oxygen species; SNCA: synuclein alpha; SQSTM1/p62: sequestosome 1; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; VDAC1/Porin: voltage dependent anion channel 1; WT: wild type

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“…Heterozygotes, however, are 5‐fold increased among patients with PD,4 and mutations in the GBA have emerged as the most common protein‐coding risk variants for PD 55.…”

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confidence: 99%

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

Liu

Boot

Locascio

et al. 2016

Annals of Neurology

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ObjectiveWe hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates.MethodsA total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.ResultsOverall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.InterpretationMutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685

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Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease

Cited by 1,862 publications

References 41 publications

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's

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