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GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease.
Hum Mol Genet 2019; 28(11):1894-1904HM

Abstract

Parkinson's disease (PD) is characterized by dopaminergic (DA) cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant (dm) mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve. Only dm mice showed a significant reduction in DA cells in the substantia nigra pars compacta, suggesting these animals were suitable for a prodromal model of PD. Next, we investigated the in vivo mechanism by which GBA insufficiency accelerates PD pathology, focusing on lipid metabolism. Dm mice showed an increased level of glucosylsphingosine without any noticeable accumulation of glucosylceramide, a direct substrate of GBA. In addition, the overexpression of asyn resulted in decreased GBA activity in mice, while dm mice tended to show an even further decreased level of GBA activity. In conclusion, we created a novel prodromal mouse model to study the disease pathogenesis and develop novel therapeutics for PD and also revealed the mechanism by which heterozygous gba deficiency contributes to PD through abnormal lipid metabolism under conditions of an altered asyn expression in vivo.

Authors+Show Affiliations

Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.Laboratory for Molecular Membrane Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.Division of Functional Genomics, Research Center for Bioscience and Technology, Faculty of Medicine, Tottori University, Tottori, Japan.Sanin Rosai Hospital, Tottori, Japan.Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.Laboratory for Molecular Membrane Neuroscience, RIKEN Brain Science Institute, Saitama, Japan.Department of Neurology Kyoto University Graduate School of Medicine, Kyoto, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30689867

Citation

Ikuno, Masashi, et al. "GBA Haploinsufficiency Accelerates Alpha-synuclein Pathology With Altered Lipid Metabolism in a Prodromal Model of Parkinson's Disease." Human Molecular Genetics, vol. 28, no. 11, 2019, pp. 1894-1904.
Ikuno M, Yamakado H, Akiyama H, et al. GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease. Hum Mol Genet. 2019;28(11):1894-1904.
Ikuno, M., Yamakado, H., Akiyama, H., Parajuli, L. K., Taguchi, K., Hara, J., ... Takahashi, R. (2019). GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease. Human Molecular Genetics, 28(11), pp. 1894-1904. doi:10.1093/hmg/ddz030.
Ikuno M, et al. GBA Haploinsufficiency Accelerates Alpha-synuclein Pathology With Altered Lipid Metabolism in a Prodromal Model of Parkinson's Disease. Hum Mol Genet. 2019 06 1;28(11):1894-1904. PubMed PMID: 30689867.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson's disease. AU - Ikuno,Masashi, AU - Yamakado,Hodaka, AU - Akiyama,Hisako, AU - Parajuli,Laxmi Kumar, AU - Taguchi,Katsutoshi, AU - Hara,Junko, AU - Uemura,Norihito, AU - Hatanaka,Yusuke, AU - Higaki,Katsumi, AU - Ohno,Kousaku, AU - Tanaka,Masaki, AU - Koike,Masato, AU - Hirabayashi,Yoshio, AU - Takahashi,Ryosuke, PY - 2018/09/13/received PY - 2019/01/21/revised PY - 2019/01/23/accepted PY - 2019/1/29/pubmed PY - 2019/1/29/medline PY - 2019/1/29/entrez SP - 1894 EP - 1904 JF - Human molecular genetics JO - Hum. Mol. Genet. VL - 28 IS - 11 N2 - Parkinson's disease (PD) is characterized by dopaminergic (DA) cell loss and the accumulation of pathological alpha synuclein (asyn), but its precise pathomechanism remains unclear, and no appropriate animal model has yet been established. Recent studies have shown that a heterozygous mutation of glucocerebrosidase (gba) is one of the most important genetic risk factors in PD. To create mouse model for PD, we crossed asyn Bacterial Artificial Chromosome transgenic mice with gba heterozygous knockout mice. These double-mutant (dm) mice express human asyn in a physiological manner through its native promoter and showed an increase in phosphorylated asyn in the regions vulnerable to PD, such as the olfactory bulb and dorsal motor nucleus of the vagus nerve. Only dm mice showed a significant reduction in DA cells in the substantia nigra pars compacta, suggesting these animals were suitable for a prodromal model of PD. Next, we investigated the in vivo mechanism by which GBA insufficiency accelerates PD pathology, focusing on lipid metabolism. Dm mice showed an increased level of glucosylsphingosine without any noticeable accumulation of glucosylceramide, a direct substrate of GBA. In addition, the overexpression of asyn resulted in decreased GBA activity in mice, while dm mice tended to show an even further decreased level of GBA activity. In conclusion, we created a novel prodromal mouse model to study the disease pathogenesis and develop novel therapeutics for PD and also revealed the mechanism by which heterozygous gba deficiency contributes to PD through abnormal lipid metabolism under conditions of an altered asyn expression in vivo. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/30689867/GBA_haploinsufficiency_accelerates_alpha_synuclein_pathology_with_altered_lipid_metabolism_in_a_prodromal_model_of_Parkinson's_disease_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddz030 DB - PRIME DP - Unbound Medicine ER -