Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease

Goris, An; Williams‐Gray, Caroline H.; Clark, Graeme R.; Foltynie, Thomas; Lewis, Simon J.G.; Brown, J. Clevedon; Ban, Masashi; Spillantini, Maria Grazia; Compston, Alastair; Burn, David J.; Chinnery, Patrick F.; Barker, Roger A.; Sawcer, Stephen

doi:10.1002/ana.21192

Cited by 261 publications

(237 citation statements)

References 43 publications

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“…[23][24][25] Previous studies have shown that genetic risk factors, including variations in microtubule-associated protein tau (MAPT), 26 ␣-synuclein (SNCA), 26 and catechol-O-methyltransferase (COMT) 27,28 may explain some of the heterogeneity in cognitive performance in PD. We and others have shown that GBA mutations are associated with cortical Lewy body pathology.…”

Section: Resultsmentioning

confidence: 99%

Cognitive performance of GBA mutation carriers with early-onset PD

Caccappolo²,

et al. 2012

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Objective: To assess the cognitive phenotype of glucocerebrosidase (GBA) mutation carriers with early-onset Parkinson disease (PD). Methods:We administered a neuropsychological battery and the University of Pennsylvania Smell Identification Test (UPSIT) to participants in the CORE-PD study who were tested for mutations in PARKIN, LRRK2, and GBA. Participants included 33 GBA mutation carriers and 60 noncarriers of any genetic mutation. Primary analyses were performed on 26 GBA heterozygous mutation carriers without additional mutations and 39 age-and PD duration-matched noncarriers. Five cognitive domains, psychomotor speed, attention, memory, visuospatial function, and executive function, were created from transformed z scores of individual neuropsychological tests. Clinical diagnoses (normal, mild cognitive impairment [MCI], dementia) were assigned blind to genotype based on neuropsychological performance and functional impairment as assessed by the Clinical Dementia Rating (CDR) score. The association between GBA mutation status and neuropsychological performance, CDR, and clinical diagnoses was assessed.

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Section: Resultsmentioning

confidence: 99%

Cognitive performance of GBA mutation carriers with early-onset PD

Caccappolo²,

et al. 2012

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“…Tau and α-synuclein likely play pivotal roles in disparate sets of neurodegenerative diseases (25). Mutations in their genes, MAPT and SNCA, that lead to formation of tau and α-synuclein, respectively, result in Alzheimer's disease, PD, DLB, and frontotemporal dementia (21,25,34). Although the mechanisms by which these proteins aggregate appear to be different, α-synuclein, for example, is spontaneously self-polymerizing (35), whereas tau requires the presence of an inducing agent (36,37).…”

Section: Discussionmentioning

confidence: 99%

Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies

Sardi¹,

Clarke²,

Viel³

et al. 2013

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

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Mutations of GBA1, the gene encoding glucocerebrosidase, represent a common genetic risk factor for developing the synucleinopathies Parkinson disease (PD) and dementia with Lewy bodies. PD patients with or without GBA1 mutations also exhibit lower enzymatic levels of glucocerebrosidase in the central nervous system (CNS), suggesting a possible link between the enzyme and the development of the disease. Previously, we have shown that early treatment with glucocerebrosidase can modulate α-synuclein aggregation in a presymptomatic mouse model of Gaucher-related synucleinopathy (Gba1 D409V/D409V) and ameliorate the associated cognitive deficit. To probe this link further, we have now evaluated the efficacy of augmenting glucocerebrosidase activity in the CNS of symptomatic Gba1 D409V/D409V mice and in a transgenic mouse model overexpressing A53T α-synuclein. Adeno-associated virus-mediated expression of glucocerebrosidase in the CNS of symptomatic Gba1 D409V/D409V mice completely corrected the aberrant accumulation of the toxic lipid glucosylsphingosine and reduced the levels of ubiquitin, tau, and proteinase K-resistant α-synuclein aggregates. Importantly, hippocampal expression of glucocerebrosidase in Gba1 D409V/D409V mice (starting at 4 or 12 mo of age) also reversed their cognitive impairment when examined using a novel object recognition test. Correspondingly, overexpression of glucocerebrosidase in the CNS of A53T α-synuclein mice reduced the levels of soluble α-synuclein, suggesting that increasing the glycosidase activity can modulate α-synuclein processing and may modulate the progression of α-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1-related and non-GBA1-associated synucleinopathies, including PD.lysosomal storage diseases | mouse models | MAPT | memory defect M utations in the gene for glucocerebrosidase (GBA1) present the highest genetic risk factor for developing synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB) (1-5). The central nervous system (CNS) of Gaucher patients and carriers who present with parkinsonism and dementia harbor deposits of α-synuclein-positive Lewy bodies (LBs) and Lewy neurites (LNs) in hippocampal neurons and their processes resembling those noted in patients with classical PD and DLB (6, 7). Aspects of these characteristics have also been noted in the CNS of several mouse models of neuropathic and nonneuropathic Gaucher disease (8-10). Consequently, a causal relationship has been suggested between the loss of glucocerebrosidase activity or the lysosomal accumulation of undegraded metabolites and the development of PD and DLB. A more direct link between glucocerebrosidase activity and α-synuclein metabolism has been highlighted by studies of Gaucher cells and mice indicating that a reduction in glucocerebrosidase activity by pharmacological or genetic interventions resulted in increased levels of α-synuclein aggregates (9-12). Moreover, a decrease in glucoce...

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“…63 Genetic variability in the a-synuclein gene is a risk factor for the development of Parkinson's disease. [64][65][66][67][68] Null mutant mice lacking a-synuclein exhibit a lower locomotor response to amphetamine, 69 whereas transgenic animals overexpressing a-synuclein display signs of motor impairment associated with a decrease in tyrosine hydroxylase levels. 70 These data suggest that a-synuclein downregulates dopaminergic neurotransmission, possibly by inhibiting tyrosine hydroxylase activity.…”

Section: Discussionmentioning

confidence: 99%

Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

et al. 2008

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A genomic region neighboring the a-synuclein gene, on rat chromosome 4, has been associated with anxiety-and alcohol-related behaviors in different rat strains. In this study, we have investigated potential molecular and physiological links between a-synuclein and the behavioral differences observed between Lewis (LEW) and Spontaneously Hypertensive (SHR) inbred rats, a genetic model of anxiety. As expected, LEW rats appeared more fearful than SHR rats in three anxiety models: open field, elevated plus maze and light/dark box. Moreover, LEW rats displayed a higher preference for alcohol and consumed higher quantities of alcohol than SHR rats. a-Synuclein mRNA and protein concentrations were higher in the hippocampus, but not the hypothalamus of LEW rats. This result inversely correlated with differences in dopamine turnover in the hippocampus of LEW and SHR rats, supporting the hypothesis that a-synuclein is important in the downregulation of dopamine neurotransmission. A novel single nucleotide polymorphism was identified in the 3 0 -untranslated region (3 0 -UTR) of the asynuclein cDNA between these two rat strains. Plasmid constructs based on the LEW 3 0 -UTR sequence displayed increased expression of a reporter gene in transiently transfected PC12 cells, in accordance with in-vivo findings, suggesting that this nucleotide exchange might participate in the differential expression of a-synuclein between LEW and SHR rats. These results are consistent with a novel role for a-synuclein in modulating rat anxiety-like behaviors, possibly through dopaminergic mechanisms. Since the behavioral and genetic differences between these two strains are the product of independent evolutionary histories, the possibility that polymorphisms in the a-synuclein gene may be associated with vulnerability to anxiety-related disorders in humans requires further investigation.

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Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease

Cited by 261 publications

References 43 publications

Cognitive performance of GBA mutation carriers with early-onset PD

Cognitive performance of GBA mutation carriers with early-onset PD

Augmenting CNS glucocerebrosidase activity as a therapeutic strategy for parkinsonism and other Gaucher-related synucleinopathies

Expression of α-synuclein is increased in the hippocampus of rats with high levels of innate anxiety

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