Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain.
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| Format: | Artículo científico |
| Language: | en |
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NPJ Parkinson's disease
2025
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| author | Choi, Zoe Yuen-Kiu Liu, Huifang Chang, Eunice Eun-Seo Pang, Shirley Yin-Yu Luo, Ivy Lingyi Ruan, Yuefei Wang, Qi Malki, Yasine Zhang, Steffi Xi-Yue Weng, Kerry Yupeng Lau, Benson Wui-Man Ng, Roy Chun-Laam Zhang, Zaijun Ho, Shu-Leong Ho, Philip Wing-Lok |
| author_facet | Choi, Zoe Yuen-Kiu Liu, Huifang Chang, Eunice Eun-Seo Pang, Shirley Yin-Yu Luo, Ivy Lingyi Ruan, Yuefei Wang, Qi Malki, Yasine Zhang, Steffi Xi-Yue Weng, Kerry Yupeng Lau, Benson Wui-Man Ng, Roy Chun-Laam Zhang, Zaijun Ho, Shu-Leong Ho, Philip Wing-Lok Choi, Zoe Yuen-Kiu Liu, Huifang Chang, Eunice Eun-Seo Pang, Shirley Yin-Yu Luo, Ivy Lingyi Ruan, Yuefei Wang, Qi Malki, Yasine Zhang, Steffi Xi-Yue Weng, Kerry Yupeng Lau, Benson Wui-Man Ng, Roy Chun-Laam Zhang, Zaijun Ho, Shu-Leong Ho, Philip Wing-Lok |
| collection | PubMed - marine biology |
| contents | Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain. Choi, Zoe Yuen-Kiu Liu, Huifang Chang, Eunice Eun-Seo Pang, Shirley Yin-Yu Luo, Ivy Lingyi Ruan, Yuefei Wang, Qi Malki, Yasine Zhang, Steffi Xi-Yue Weng, Kerry Yupeng Lau, Benson Wui-Man Ng, Roy Chun-Laam Zhang, Zaijun Ho, Shu-Leong Ho, Philip Wing-Lok Brain accumulation of toxic soluble α-synuclein (α-syn) oligomers represents a prodromal marker of synucleinopathies in Parkinson's disease (PD), contributing to progressive nigrostriatal neurodegeneration. Dysfunction in beta-glucocerebrosidase (GCase) and leucine-rich repeat kinase 2 (LRRK2) mutation are genetic risks for developing synucleinopathies. However, whether pharmacological GCase activation ameliorated synucleinopathies in LRRK2-PD was unexplored. Here, we showed that long-term treatment of ambroxol (ABX), a brain-penetrant GCase activator, reduced α-syn oligomer accumulation in aged mutant LRRK2 mouse striatum. Acute ABX treatment (50 µM) increased cellular GCase enzymatic activity and reduced Ser129-α-syn phosphorylation in human SH-SY5Y cells and mutant LRRK2 mouse fibroblasts, independent to LRRK2 kinase activity. Real-time DQ-BSA assay revealed lysosomal dysfunction in mutant MEFs, which was partially attenuated by ABX treatment. Lysosomal stress by bafilomycin-A1 induced endogenous GCase activity in wildtype (WT) MEFs, which was not observed in the LRRK2 mutant. Single gavage of ABX (400 mg/kg) in aged mice achieved peak drug level in serum and brain within 6 h post-administration. Ad libitum feeding of ABX (in food pellets) over 18 weeks (average dose: 45.9 mg/kg/day) elevated brain GCase activity in both WT and mutant striatum without affecting body weight. This regimen significantly reduced α-syn oligomer level in mutant striatum to a comparable physiological level in age-matched WT without altering total α-syn and Ser129-phosphorylation levels. This is the first study demonstrating reduced α-syn oligomer accumulation by chronic treatment of GCase activator in aged mouse brains vulnerable to PD, suggesting early intervention to alter progression of synucleinopathies as a key determinant of clinical outcomes of PD. |
| format | Artículo científico |
| id | pubmed_41388030 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | NPJ Parkinson's disease |
| record_format | pubmed |
| spellingShingle | Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain. Choi, Zoe Yuen-Kiu Liu, Huifang Chang, Eunice Eun-Seo Pang, Shirley Yin-Yu Luo, Ivy Lingyi Ruan, Yuefei Wang, Qi Malki, Yasine Zhang, Steffi Xi-Yue Weng, Kerry Yupeng Lau, Benson Wui-Man Ng, Roy Chun-Laam Zhang, Zaijun Ho, Shu-Leong Ho, Philip Wing-Lok Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain. Choi, Zoe Yuen-Kiu Liu, Huifang Chang, Eunice Eun-Seo Pang, Shirley Yin-Yu Luo, Ivy Lingyi Ruan, Yuefei Wang, Qi Malki, Yasine Zhang, Steffi Xi-Yue Weng, Kerry Yupeng Lau, Benson Wui-Man Ng, Roy Chun-Laam Zhang, Zaijun Ho, Shu-Leong Ho, Philip Wing-Lok Brain accumulation of toxic soluble α-synuclein (α-syn) oligomers represents a prodromal marker of synucleinopathies in Parkinson's disease (PD), contributing to progressive nigrostriatal neurodegeneration. Dysfunction in beta-glucocerebrosidase (GCase) and leucine-rich repeat kinase 2 (LRRK2) mutation are genetic risks for developing synucleinopathies. However, whether pharmacological GCase activation ameliorated synucleinopathies in LRRK2-PD was unexplored. Here, we showed that long-term treatment of ambroxol (ABX), a brain-penetrant GCase activator, reduced α-syn oligomer accumulation in aged mutant LRRK2 mouse striatum. Acute ABX treatment (50 µM) increased cellular GCase enzymatic activity and reduced Ser129-α-syn phosphorylation in human SH-SY5Y cells and mutant LRRK2 mouse fibroblasts, independent to LRRK2 kinase activity. Real-time DQ-BSA assay revealed lysosomal dysfunction in mutant MEFs, which was partially attenuated by ABX treatment. Lysosomal stress by bafilomycin-A1 induced endogenous GCase activity in wildtype (WT) MEFs, which was not observed in the LRRK2 mutant. Single gavage of ABX (400 mg/kg) in aged mice achieved peak drug level in serum and brain within 6 h post-administration. Ad libitum feeding of ABX (in food pellets) over 18 weeks (average dose: 45.9 mg/kg/day) elevated brain GCase activity in both WT and mutant striatum without affecting body weight. This regimen significantly reduced α-syn oligomer level in mutant striatum to a comparable physiological level in age-matched WT without altering total α-syn and Ser129-phosphorylation levels. This is the first study demonstrating reduced α-syn oligomer accumulation by chronic treatment of GCase activator in aged mouse brains vulnerable to PD, suggesting early intervention to alter progression of synucleinopathies as a key determinant of clinical outcomes of PD. |
| title | Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain. |
| url | https://pubmed.ncbi.nlm.nih.gov/41388030/ |