고한석 (The Johns Hopkins University School of Medicine, Diana Helis Henry Medical Research Foundation, Adrienne Helis Malvin Medical Research Foundation ) | 한빛사논문 > 한빛사

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The Johns Hopkins University School of Medicine, Diana Helis Henry Medical Research Foundation, Adrienne Helis Malvin Medical Research Foundation

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Acta Neuropathol. Commun., Published: 27 April 2018 | https://doi.org/10.1186/s40478-018-0538-9 D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model

Donghoon Kim^1,2, Heehong Hwang¹, Seulah Choi¹, Sang Ho Kwon¹, Suhyun Lee¹, Jae Hong Park¹, SangMin Kim¹ and Han Seok Ko^1,2,3,4*

¹Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

²Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

³Diana Helis Henry Medical Research Foundation, New Orleans, Louisiana 70130, USA.

⁴Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130, USA

^*Correspondence : Han Seok Ko

Abstract

Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson’s disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice. Here, we show that GBA1 enzyme activity plays a significant role in the hA53T α-synuclein induced α-synucleinopathy. The expression of D409H GBA1 markedly shortens the lifespan of hA53T α-synuclein transgenic mice. Moreover, D409H GBA1 expression exacerbates the formation of insoluble aggregates of α-synuclein, glial activation, neuronal degeneration, and motor abnormalities in the hA53T α-synuclein transgenic mice. Interestingly, the expression of D409H GBA1 results in the loss of dopaminergic neurons in the substantia nigra pars compacta of hA53T transgenic mice. Taken together, these results indicate that GBA1 deficiency due to D409H mutation affects the disease onset and course in hA53T α-synuclein transgenic mice. Therefore, strategies aimed to maintain GBA1 enzyme activity could be employed to develop an effective novel therapy for GBA1 linked-PD and related α-synucleinopathies.

Keywords : Parkinson’s disease, Gaucher’s disease, Glucocerebrosidase 1, D409H GBA1 mutation, α-synuclein

논문정보

형식Research article
게재일2018년 04월 (BRIC 등록일 2018-08-06)
연구진국외 연구진
분야 생명과학 > 신경생물학
구분구・추천논문

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