Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 9, Pages 3537-3542Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220464110
Keywords
lysosomal storage diseases; mouse models; MAPT; memory defect
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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 alpha-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 alpha-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 a-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 alpha-synuclein mice reduced the levels of soluble alpha-synuclein, suggesting that increasing the glycosidase activity can modulate alpha-synuclein processing and may modulate the progression of alpha-synucleinopathies. Hence, increasing glucocerebrosidase activity in the CNS represents a potential therapeutic strategy for GBA1/-related and non-GBA1-associated synucleinopathies, including PD.
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