A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

Nalls, Michael A.; Durán, Raquel; Lopez, Grisel; Kurzawa‐Akanbi, Marzena; McKeith, Ian G.; Chinnery, Patrick F.; Morris, Christopher M.; Theuns, Jessie; Crosiers, David; Cras, Patrick; Engelborghs, Sebastiaan; Deyn, Peter Paul De; Broeckhoven, Christine Van; Mann, David; Snowden, Julie S.; Pickering‐Brown, Stuart; Halliwell, Nicola; Davidson, Yvonne; Gibbons, Linda; Harris, Jenny; Sheerin, Una Marie; Brás, José; Hardy, John; Clark, Lorraine N.; Marder, Karen; Honig, Lawrence S.; Berg, Daniela; Maetzler, Walter; Brockmann, Kathrin; Gasser, Thomas; Novellino, Fabiana; Quattrone, Aldo; Annesi, Grazia; Marco, Elvira Valeria De; Rogaeva, Ekaterina; Masellis, Mario; Black, Sandra E.; Bilbao, Juan M.; Foroud, Tatiana; Ghetti, Bernardino; Nichols, William C.; Pankratz, Nathan; Halliday, Glenda M.; Lesage, Suzanne; Klebe, Stephan; Dürr, Alexandra; Duyckaerts, Charles; Brice, Alexis; Giasson, Benoit I.; Trojanowski, John Q.; Hurtig, Howard I.; Tayebi, Nahid; Landazabal, Claudia; Knight, Melanie A.; Keller, Margaux F.; Singleton, Andrew B.; Wolfsberg, Tyra G.; Sidransky, Ellen

doi:10.1001/jamaneurol.2013.1925

Cited by 371 publications

(335 citation statements)

References 31 publications

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“…This association was stronger than the association of GBA mutations with PD in a similar population (Noreau, et al, 2011), suggesting that GBA may be one of the genetic factors that is more specific to RBD. Furthermore, the association of GBA mutations with DLB (Nalls, et al, 2013) also seems to be stronger than the association with PD (Sidransky, et al, 2009). …”

Section: Introductionmentioning

confidence: 92%

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

Gan‐Or

Montplaisir

Ross

et al. 2017

Neurobiology of Aging

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The dementia-associated APOE ε4 allele is not associated with REM sleep behavior disorder, Neurobiology of Aging (2016Aging ( ), doi: 10.1016Aging ( /j.neurobiolaging.2016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPTAbstract: The current study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic REM sleep behavior disorder (RBD). Two SNPs, rs429358 and rs7412, were genotyped in RBD patients (n=480) and in controls (n=823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR=1.11, 95% CI 0.88-1.40, p=0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to PD (0.12) or multiple system atrophy (0.14, p=1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies.

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Section: Introductionmentioning

confidence: 92%

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

Gan‐Or

Montplaisir

Ross

et al. 2017

Neurobiology of Aging

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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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“…Mutations in the glucocerebrosidase gene (GBA) are the highest genetic risk factor for developing PD and DLB (1,2). Recent clinical studies indicate that GBA status may also impact the natural history of PD.…”

mentioning

confidence: 99%

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Sardi

Viel

Clarke

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

167

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Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba D409V/D409V and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment of Gba D409V/D409V mice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment of A53T-SNCA mice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a diseasemodifying therapeutic strategy for GBA-related synucleinopathies and conceivably for certain forms of sporadic disease.Parkinson's disease | GBA mutations | glucosylceramide synthase | Gaucher disease | Lewy body dementia

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A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies

Cited by 371 publications

References 31 publications

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

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