溶酶体pH稳态与帕金森病
Lysosomal pH Homeostasis and Parkinson’s Disease
DOI: 10.12677/acm.2024.1451672, PDF,   
作者: 温 娜, 陈丹桢：浙江工业大学长三角绿色制药协同创新中心，浙江 杭州
关键词: 溶酶体酸化；溶酶体；帕金森病；Lysosomal Acidity； Lysosome； Parkinson’s Disease
摘要: 溶酶体酸化功能障碍被认为是帕金森病的关键驱动因素。多种遗传因素通过损害溶酶体膜上的V-ATPase质子泵和离子通道功能影响溶酶体酸化。虽然溶酶体酸化影响帕金森病进展的潜在机制仍不清楚，但最近的研究表明，溶酶体酸化功能损伤早发于神经退行性病变和帕金森病病理晚期。本文通过对当前已经存在的溶酶体酸化和帕金森病细胞层面及小鼠体内表型的研究进行总结，从而提出恢复溶酶体pH可作为延缓帕金森病进展或治疗帕金森病的方案。
Abstract: Lysosomal acidification dysfunction is considered to be a key driver of Parkinson’s disease. A variety of genetic factors affect lysosomal acidification by damaging the function of V-ATPase proton pump and ion channels on the lysosomal limiting membranes. Although the potential mechanism of lysosomal acidification affecting the progression of Parkinson’s disease is still unclear, recent studies have shown that lysosomal acidification damage occurs early in neurodegenerative lesions and late pathological stages of Parkinson’s disease. This paper summarizes the existing studies on lysosomal acidification and phenotypes of Parkinson’s disease over cellular level and mice, and proposes that the restoration of lysosomal pH can be used as a scheme to delay the progression of Parkinson’s disease or to rescue Parkinson’s disease.
文章引用：温娜, 陈丹桢. 溶酶体pH稳态与帕金森病[J]. 临床医学进展, 2024, 14(5): 2215-2220. https://doi.org/10.12677/acm.2024.1451672

参考文献

[1] The Lancet (2024) What Next in Parkinson’s Disease? The Lancet, 403, 219. [Google Scholar] [CrossRef] 
[2] Webb, J.L., Ravikumar, B., et al. (2003) Alpha-Synuclein Is Degraded by both Autophagy and the Proteasome. Journal of Biological Chemistry, 278, 25009-25013. [Google Scholar] [CrossRef] 
[3] Xu, H. and Ren, D. (2015) Lysosomal Physiology. Annual Review of Physiology, 77, 57-80. [Google Scholar] [CrossRef] [PubMed]
[4] Butor, C., Griffiths, G., et al. (1995) Co-Localization of Hydrolytic Enzymes with Widely Disparate pH Optima: Implications for the Regulation of Lysosomal pH. Journal of Cell Science, 108, 2213-2219. [Google Scholar] [CrossRef] [PubMed]
[5] Mindell, J.A. (2012) Lysosomal Acidification Mechanisms. Annual Review of Physiology, 74, 69-86. [Google Scholar] [CrossRef] [PubMed]
[6] Hu, M.Q., et al. (2024) The Ion Channels of Endomembranes. Physiological Reviews, 104, 1335-1385.
[7] Hu, M., Li, P., Wang, C., et al. (2022) Parkinson’s Disease-Risk Protein TMEM175 Is a Proton-Activated Proton Channel in Lysosomes. Cell, 185, 2292-2308.E20. [Google Scholar] [CrossRef] [PubMed]
[8] Gibb, W.R. and Lees, A.J. (1988) The Relevance of the Lewy Body to the Pathogenesis of Idiopathic Parkinson’s Disease. Journal of Neurology, Neurosurgery & Psychiatry, 51, 745-752. [Google Scholar] [CrossRef] [PubMed]
[9] Tozzi, A., Sciaccaluga, M., Loffredo, V., et al. (2021) Dopamine-Dependent Early Synaptic and Motor Dysfunctions Induced by α-Synuclein in the Nigrostriatal Circuit. Brain, 144, 3477-3491. [Google Scholar] [CrossRef] [PubMed]
[10] Calo, L., Wegrzynowicz, M., Santivanez-Perez, J., et al. (2016) Synaptic Failure and Alpha-Synuclein. Movement Disorders, 31, 169-177. [Google Scholar] [CrossRef] [PubMed]
[11] Schweighauser, M., et al. (2020) Structures of α-Synuclein Filaments from Multiple System Atrophy. Nature, 585, 464-469. [Google Scholar] [CrossRef] [PubMed]
[12] Morris, H.R., Spillantini, M.G., Sue, C.M., et al. (2024) The Pathogenesis of Parkinson’s Disease. The Lancet, 403, 293-304. [Google Scholar] [CrossRef] 
[13] Guo, Y., Sun, Y., Song, Z., et al. (2021) Genetic Analysis and Literature Review of SNCA Variants in Parkinson’s Disease. Frontiers in Aging Neuroscience, 13, Article ID: 648151. [Google Scholar] [CrossRef] [PubMed]
[14] Ben-Shlomo, Y., Darweesh, S., Llibre-Guerra, J., et al. (2024) The Epidemiology of Parkinson’s Disease. The Lancet, 403, 283-292. [Google Scholar] [CrossRef] 
[15] Horowitz, M., Braunstein, H., Zimran, A., et al. (2022) Lysosomal Functions and Dysfunctions: Molecular and Cellular Mechanisms Underlying Gaucher Disease and Its Association with Parkinson Disease. Advanced Drug Delivery Reviews, 187, Article ID: 114402. [Google Scholar] [CrossRef] [PubMed]
[16] Navarro-Romero, A., Montpeyo, M. and Martinez-Vicente, M. (2020) The Emerging Role of the Lysosome in Parkinson’s Disease. Cells, 9, Article No. 2399. [Google Scholar] [CrossRef] [PubMed]
[17] Vogiatzi, T., Xilouri, M., et al. (2008) Wild Type Alpha-Synuclein Is Degraded by Chaperone-Mediated Autophagy and Macroautophagy in Neuronal Cells. Journal of Biological Chemistry, 283, 23542-23556. [Google Scholar] [CrossRef] 
[18] Dehay, B., Martinez-Vicente, M., et al. (2013) Lysosomal Impairment in Parkinson’s Disease. Movement Disorders, 28, 725-732. [Google Scholar] [CrossRef] [PubMed]
[19] Dehay, B., Ramirez, A., et al. (2012) Loss of P-Type ATPase ATP13A2/PARK9 Function Induces General Lysosomal Deficiency and Leads to Parkinson Disease Neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 109, 9611-9616. [Google Scholar] [CrossRef] [PubMed]
[20] Schultheis, P.J., Fleming, S., et al. (2013) Atp13a2-Deficient Mice Exhibit Neuronal Ceroid Lipofuscinosis, Limited α-Synuclein Accumulation and Age-Dependent Sensorimotor Deficits. Human Molecular Genetics, 22, 2067-2082. [Google Scholar] [CrossRef] [PubMed]
[21] Wallings, R., Connor-Robson, N. and Wade-Martins, R. (2019) LRRK2 Interacts with the Vacuolar-Type H -ATPase Pump A1 Subunit to Regulate Lysosomal Function. Human Molecular Genetics, 28, 2696-2710. [Google Scholar] [CrossRef] [PubMed]
[22] Henry, A.G., Aghamohammadzadeh, S., Samaroo, H., et al. (2015) Pathogenic LRRK2 Mutations, through Increased Kinase Activity, Produce Enlarged Lysosomes with Reduced Degradative Capacity and Increase ATP13A2 Expression. Human Molecular Genetics, 24, 6013-6028. [Google Scholar] [CrossRef] [PubMed]
[23] Dehay, B., BovE, J., et al. (2010) Pathogenic Lysosomal Depletion in Parkinson’s Disease. Journal of Neuroscience, 30, 12535-12544. [Google Scholar] [CrossRef] 
[24] Vest, R.T., Chou, C.C., Zhang, H., et al. (2022) Small Molecule C381 Targets the Lysosome to Reduce Inflammation and Ameliorate Disease in Models of Neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 119, E2121609119. [Google Scholar] [CrossRef] [PubMed]
[25] Rahman, N., Ramos-Espiritu, L., Milner, T.A., et al. (2016) Soluble Adenylyl Cyclase Is Essential for Proper Lysosomal Acidification. Journal of General Physiology, 148, 325-339. [Google Scholar] [CrossRef] [PubMed]
[26] Bonam, S.R., Wang, F. and Muller, S. (2019) Lysosomes as a Therapeutic Target. Nature Reviews Drug Discovery, 18, 923-948. [Google Scholar] [CrossRef] [PubMed]
[27] Tong, B.C., Huang, A.S., Wu, A.J., et al. (2022) Tetrandrine Ameliorates Cognitive Deficits and Mitigates Tau Aggregation in Cell and Animal Models of Tauopathies. Journal of Biomedical Science, 29, Article No. 85. [Google Scholar] [CrossRef] [PubMed]
[28] Yao, X.C., Xue, X., Zhang, H.T., et al. (2019) Pseudoginsenoside-F11 Alleviates Oligomeric β-Amyloid-Induced Endosome-Lysosome Defects in Microglia. Traffic, 20, 61-70. [Google Scholar] [CrossRef] [PubMed]
[29] Chin, M., Ang, K.H., Davies, J., et al. (2022) Phenotypic Screening Using High-Content Imaging to Identify Lysosomal pH Modulators in a Neuronal Cell Model. ACS Chemical Neuroscience, 13, 1505-1516. [Google Scholar] [CrossRef] [PubMed]
[30] Bordi, M., Berg, M.J., Mohan, P.S., et al. (2016) Autophagy Flux in CA1 Neurons of Alzheimer Hippocampus: Increased Induction Overburdens Failing Lysosomes to Propel Neuritic Dystrophy. Autophagy, 12, 2467-2483. [Google Scholar] [CrossRef] [PubMed]
[31] Lo, C.H., Skarica, M., Mansoor, M., et al. (2021) Astrocyte Heterogeneity in Multiple Sclerosis: Current Understanding and Technical Challenges. Frontiers in Cellular Neuroscience, 15, Article ID: 726479. [Google Scholar] [CrossRef] [PubMed]

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