D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model
| Autor: | Suhyun Lee, Jae Hong Park, Dong-Hoon Kim, Sang Ho Kwon, Han Seok Ko, Heehong Hwang, SangMin Kim, Seulah Choi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Parkinson's disease medicine.disease_cause lcsh:RC346-429 Mice 0302 clinical medicine D409H GBA1 mutation Mutation Gaucher’s disease Parkinsonism Endoplasmic Reticulum Stress Disease Progression alpha-Synuclein Glucosylceramidase Genetically modified mouse Tyrosine 3-Monooxygenase Longevity Substantia nigra Mice Transgenic Biology Motor Activity Pathology and Forensic Medicine 03 medical and health sciences Cellular and Molecular Neuroscience α-synuclein Glucocerebrosidase 1 Glial Fibrillary Acidic Protein medicine Animals Humans Histidine lcsh:Neurology. Diseases of the nervous system Aspartic Acid Gaucher Disease Dementia with Lewy bodies Pars compacta Research medicine.disease nervous system diseases Mice Inbred C57BL 030104 developmental biology nervous system Gene Expression Regulation Cancer research Parkinson’s disease Neurology (clinical) Glucocerebrosidase 030217 neurology & neurosurgery Brain Stem |
| Zdroj: | Acta Neuropathologica Communications Acta Neuropathologica Communications, Vol 6, Iss 1, Pp 1-12 (2018) |
| ISSN: | 2051-5960 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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