Ataxin-3 Overexpression via Adeno-associated Viral Vector Injection in the Primate Cerebellum: A Novel Model of Spinocerebellar Ataxia Type 3
10.5607/en25031
- Author:
Keonwoo KIM
;
Aryun KIM
;
Jinyoung WON
;
Junghyung PARK
;
Kyung Seob LIM
;
Chang-Yeop JEON
;
Jisun MIN
;
Jee-Hyun CHO
;
Youngkyu SONG
;
Bon-Sang KOO
;
Gyu-Seo BAE
;
Eunsu JEON
;
Kang-Jin JEONG
;
Sung-Hyun PARK
;
Hwal-Yong LEE
;
Won Seok CHOI
;
Dong-Seok LEE
;
Youngjeon LEE
- Publication Type:Original Article
- From:Experimental Neurobiology
2025;34(6):248-262
- CountryRepublic of Korea
- Language:English
-
Abstract:
Spinocerebellar ataxia type 3 (SCA3) is an autosomal-dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in the ataxin-3 gene. The resulting mutant ataxin-3 protein forms intraneuronal inclusions that lead to neurodegeneration in the cerebellum and other brain regions. This study aimed to develop a novel nonhuman primate model of SCA3 to address the limitations of existing knock-in and transgenic models using an adeno-associated virus (AAV) to deliver the mutant gene. AAV viral vectors carrying mutant ataxin-3 were stereotaxically injected into the cerebellum of monkeys. The animals were monitored over an 8-week period, during which behavioral and neuroimaging assessments were conducted. This was followed by a detailed pathological examination. The AAV vector successfully spread throughout the cerebellum, and the expression of mutant ataxin-3 was confirmed. Neuroimaging revealed a reduction in N-acetylaspartate (NAA) levels, whereas histological analysis showed significant damage to the Purkinje cell layer. Notably, the monkeys exhibited sleep disturbances, a prodromal symptom commonly observed in human patients with SCA3. AAV-mediated delivery of mutant ataxin-3 can effectively replicate the key pathological and clinical features of SCA3 in primates. This approach offers a promising new model for studying disease mechanisms and evaluating potential therapies.
