PSAP基因相关帕金森病研究进展
Research Progress on the PSAP Gene Related Parkinson’s Disease
DOI: 10.12677/acm.2026.1631210, PDF,   
作者: 李 璐, 武 衡*：南华大学附属第一医院神经内科，湖南 衡阳
关键词: 帕金森病；PSAP；溶酶体功能；基本功能；发病机制；Parkinson’s Disease； PSAP； Lysosomal Function； Basic Function； Pathogenesis
摘要: 帕金森病(Parkinson’s disease, PD)是一种常见的神经退行性疾病，其典型病理特征为中脑黑质致密部多巴胺能(Dopamine, DA)神经元的进行性丢失，以及α-突触核蛋白(Alpha-synuclein, α-syn)异常聚集并形成路易小体(Lewy bodies, LBs)。近年来，越来越多的研究表明，溶酶体功能障碍在PD的发生与进展中发挥重要作用。PSAP (Prosaposin)基因是溶酶体功能调控网络中的关键分子，可通过影响溶酶体水解酶活性、维持溶酶体膜稳定性以及调控自噬–溶酶体通路的完整性，参与PD的病理过程。基于此，本文系统综述PSAP基因/蛋白的结构和功能、PSAP基因在PD中的流行病学、PSAP基因相关PD的临床特征、PSAP基因变异参与PD发病的分子机制及靶向治疗，旨在为深入理解PD的分子病理基础及开发靶向干预策略提供理论依据。
Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain and the abnormal aggregation of α-synuclein into Lewy bodies (LBs). In recent years, accumulating evidence has highlighted the critical role of lysosomal dysfunction in the pathogenesis and progression of PD. The PSAP (prosaposin) gene is a key component of the lysosomal regulatory network and participates in PD-related pathological processes by modulating lysosomal hydrolase activity, maintaining lysosomal membrane stability, and regulating the integrity of the autophagy-lysosome pathway. In this review, we systematically summarize the structure and function of the PSAP gene/protein, the epidemiological evidence linking PSAP to PD, the clinical characteristics of PSAP-related PD, the molecular mechanisms by which PSAP variants contribute to PD pathogenesis, and emerging therapeutic strategies targeting this pathway. This work aims to provide a theoretical framework for a deeper understanding of the molecular pathology of PD and to facilitate the development of targeted intervention strategies.
文章引用：李璐, 武衡. PSAP基因相关帕金森病研究进展[J]. 临床医学进展, 2026, 16(3): 3992-3999. https://doi.org/10.12677/acm.2026.1631210

参考文献

[1] Kouli, A., Torsney, K.M. and Kuan, W.L. (2018) Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis. In: Stoker, T.B. and Greenland, J.C., Eds., Parkinson’s Disease: Pathogenesis and Clinical Aspects, Codon Publications, 4.
[2] Yang, Y. and Zhang, Z. (2023) α-Synuclein Pathology from the Body to the Brain: So Many Seeds So Close to the Central Soil. Neural Regeneration Research, 19, 1463-1472. [Google Scholar] [CrossRef] [PubMed]
[3] Blauwendraat, C., Nalls, M.A. and Singleton, A.B. (2020) The Genetic Architecture of Parkinson’s Disease. The Lancet Neurology, 19, 170-178. [Google Scholar] [CrossRef] [PubMed]
[4] Tanner, C.M. and Ostrem, J.L. (2024) Parkinson’s Disease. New England Journal of Medicine, 391, 442-452. [Google Scholar] [CrossRef] [PubMed]
[5] Senkevich, K. and Gan-Or, Z. (2020) Autophagy Lysosomal Pathway Dysfunction in Parkinson’s Disease; Evidence from Human Genetics. Parkinsonism & Related Disorders, 73, 60-71. [Google Scholar] [CrossRef] [PubMed]
[6] Oji, Y., Hatano, T., Ueno, S., Funayama, M., Ishikawa, K., Okuzumi, A., et al. (2020) Variants in Saposin D Domain of Prosaposin Gene Linked to Parkinson’s Disease. Brain, 143, 1190-1205. [Google Scholar] [CrossRef] [PubMed]
[7] O’Brien, J.S. and Kishimoto, Y. (1991) Saposin Proteins: Structure, Function, and Role in Human Lysosomal Storage Disorders. The FASEB Journal, 5, 301-308. [Google Scholar] [CrossRef] [PubMed]
[8] Li, X. and Guo, L. (2025) Prosaposin: A Multifaceted Protein Orchestrating Biological Processes and Diseases. Cells, 14, Article 1131. [Google Scholar] [CrossRef] [PubMed]
[9] Cesani, M., Lorioli, L., Grossi, S., Amico, G., Fumagalli, F., Spiga, I., et al. (2015) Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Human Mutation, 37, 16-27. [Google Scholar] [CrossRef] [PubMed]
[10] Kishimoto, Y., Hiraiwa, M. and O’Brien, J. (1992) Saposins: Structure, Function, Distribution, and Molecular Genetics. Journal of Lipid Research, 33, 1255-1267. [Google Scholar] [CrossRef] 
[11] Hiraiwa, M., Martin, B.M., Kishimoto, Y., Conner, G.E., Tsuji, S. and O’Brien, J.S. (1997) Lysosomal Proteolysis of Prosaposin, the Precursor of Saposins (Sphingolipid Activator Proteins): Its Mechanism and Inhibition by Ganglioside. Archives of Biochemistry and Biophysics, 341, 17-24. [Google Scholar] [CrossRef] [PubMed]
[12] Hiraiwa, M., Soeda, S., Kishimoto, Y. and O’Brien, J.S. (1992) Binding and Transport of Gangliosides by Prosaposin. Proceedings of the National Academy of Sciences of the United States of America, 89, 11254-11258. [Google Scholar] [CrossRef] [PubMed]
[13] Ahn, V.E., Faull, K.F., Whitelegge, J.P., Fluharty, A.L. and Privé, G.G. (2002) Crystal Structure of Saposin B Reveals a Dimeric Shell for Lipid Binding. Proceedings of the National Academy of Sciences of the United States of America, 100, 38-43. [Google Scholar] [CrossRef] [PubMed]
[14] Kolter, T. and Sandhoff, K. (2009) Lysosomal Degradation of Membrane Lipids. FEBS Letters, 584, 1700-1712. [Google Scholar] [CrossRef] [PubMed]
[15] Yoneshige, A., Suzuki, K., Suzuki, K. and Matsuda, J. (2010) A Mutation in the Saposin C Domain of the Sphingolipid Activator Protein (Prosaposin) Gene Causes Neurodegenerative Disease in Mice. Journal of Neuroscience Research, 88, 2118-2134. [Google Scholar] [CrossRef] [PubMed]
[16] Diaz-Font, A., Cormand, B., Santamaria, R., Vilageliu, L., Grinberg, D. and Chabás, A. (2005) A Mutation within the Saposin D Domain in a Gaucher Disease Patient with Normal Glucocerebrosidase Activity. Human Genetics, 117, 275-277. [Google Scholar] [CrossRef] [PubMed]
[17] Matsuda, J., Vanier, M.T., Saito, Y., Tohyama, J., Suzuki, K. and Suzuki, K. (2001) A Mutation in the Saposin a Domain of the Sphingolipid Activator Protein (Prosaposin) Gene Results in a Late-Onset, Chronic Form of Globoid Cell Leukodystrophy in the Mouse. Human Molecular Genetics, 10, 1191-1199. [Google Scholar] [CrossRef] [PubMed]
[18] Sun, Y., Witte, D.P., Zamzow, M., Ran, H., Quinn, B., Matsuda, J., et al. (2007) Combined Saposin C and D Deficiencies in Mice Lead to a Neuronopathic Phenotype, Glucosylceramide and α-Hydroxy Ceramide Accumulation, and Altered Prosaposin Trafficking. Human Molecular Genetics, 16, 957-971. [Google Scholar] [CrossRef] [PubMed]
[19] Oji, Y., Hatano, T., Funayama, M. and Hattori, N. (2020) Reply: Saposin D Variants Are Not a Common Cause of Familial Parkinson’s Disease among Italians; and Lack of Evidence for Genetic Association of Saposins A, B, C and D with Parkinson’s Disease. Brain, 143, e73-e73. [Google Scholar] [CrossRef] [PubMed]
[20] O’Brien, J.S., Carson, G.S., Seo, H.C., Hiraiwa, M. and Kishimoto, Y. (1994) Identification of Prosaposin as a Neurotrophic Factor. Proceedings of the National Academy of Sciences of the United States of America, 91, 9593-9596. [Google Scholar] [CrossRef] [PubMed]
[21] Filocamo, M. and Morrone, A. (2011) Lysosomal Storage Disorders: Molecular Basis and Laboratory Testing. Human Genomics, 5, 156-169. [Google Scholar] [CrossRef] [PubMed]
[22] Deng, H., Xiu, X. and Jankovic, J. (2014) Genetic Convergence of Parkinson’s Disease and Lysosomal Storage Disorders. Molecular Neurobiology, 51, 1554-1568. [Google Scholar] [CrossRef] [PubMed]
[23] Robak, L.A., Jansen, I.E., van Rooij, J., Uitterlinden, A.G., Kraaij, R., Jankovic, J., et al. (2017) Excessive Burden of Lysosomal Storage Disorder Gene Variants in Parkinson’s Disease. Brain, 140, 3191-3203. [Google Scholar] [CrossRef] [PubMed]
[24] Ouled Amar Bencheikh, B., Leveille, E., Ruskey, J.A., Spiegelman, D., Liong, C., Fon, E.A., et al. (2018) Sequencing of the GBA Coactivator, Saposin C, in Parkinson Disease. Neurobiology of Aging, 72, 187.e1-187.e3. [Google Scholar] [CrossRef] [PubMed]
[25] Sidransky, E. and Lopez, G. (2012) The Link between the GBA Gene and Parkinsonism. The Lancet Neurology, 11, 986-998. [Google Scholar] [CrossRef] [PubMed]
[26] Chen, Y., Gu, X., Ou, R., Zhang, L., Hou, Y., Liu, K., et al. (2020) Genetic Analysis of Prosaposin, the Lysosomal Storage Disorder Gene in Parkinson’s Disease. Molecular Neurobiology, 58, 1583-1592. [Google Scholar] [CrossRef] [PubMed]
[27] Chaudhuri, K.R., Healy, D.G. and Schapira, A.H. (2006) Non-Motor Symptoms of Parkinson’s Disease: Diagnosis and Management. The Lancet Neurology, 5, 235-245. [Google Scholar] [CrossRef] [PubMed]
[28] Shachar, T., Bianco, C.L., Recchia, A., Wiessner, C., Raas‐Rothschild, A. and Futerman, A.H. (2011) Lysosomal Storage Disorders and Parkinson’s Disease: Gaucher Disease and Beyond. Movement Disorders, 26, 1593-1604. [Google Scholar] [CrossRef] [PubMed]
[29] Dehay, B., Martinez‐Vicente, M., Caldwell, G.A., Caldwell, K.A., Yue, Z., Cookson, M.R., et al. (2013) Lysosomal Impairment in Parkinson’s Disease. Movement Disorders, 28, 725-732. [Google Scholar] [CrossRef] [PubMed]
[30] Burlina, A.P., Manara, R. and Gueraldi, D. (2024) Lysosomal Storage Diseases. Handbook of Clinical Neurology, 204, 147-172.
[31] He, Y., Kaya, I., Shariatgorji, R., Lundkvist, J., Wahlberg, L.U., Nilsson, A., et al. (2023) Prosaposin Maintains Lipid Homeostasis in Dopamine Neurons and Counteracts Experimental Parkinsonism in Rodents. Nature Communications, 14, Article No. 5804. [Google Scholar] [CrossRef] [PubMed]
[32] Ruz, C., Barrero, F.J., Pelegrina, J., Bandrés-Ciga, S., Vives, F. and Duran, R. (2022) Saposin C, Key Regulator in the α-Synuclein Degradation Mediated by Lysosome. International Journal of Molecular Sciences, 23, Article 12004. [Google Scholar] [CrossRef] [PubMed]
[33] Kashiba, M., Oizumi, M., Suzuki, M., Sawamura, Y., Nagashima, K., Yoshimura, S., et al. (2014) Prosaposin Regulates Coenzyme Q10 Levels in HepG2 Cells, Especially Those in Mitochondria. Journal of Clinical Biochemistry and Nutrition, 55, 85-89. [Google Scholar] [CrossRef] [PubMed]
[34] Plotegher, N. and Duchen, M.R. (2017) Mitochondrial Dysfunction and Neurodegeneration in Lysosomal Storage Disorders. Trends in Molecular Medicine, 23, 116-134. [Google Scholar] [CrossRef] [PubMed]
[35] Exner, N., Lutz, A.K., Haass, C. and Winklhofer, K.F. (2012) Mitochondrial Dysfunction in Parkinson’s Disease: Molecular Mechanisms and Pathophysiological Consequences. The EMBO Journal, 31, 3038-3062. [Google Scholar] [CrossRef] [PubMed]
[36] Hassanzadeh Ghassabeh, G., De Baetselier, P., Brys, L., Noël, W., Van Ginderachter, J.A., Meerschaut, S., et al. (2006) Identification of a Common Gene Signature for Type II Cytokine-Associated Myeloid Cells Elicited in Vivo in Different Pathologic Conditions. Blood, 108, 575-583. [Google Scholar] [CrossRef] [PubMed]
[37] Kojima, R., Zurbruegg, M., Li, T., Paslawski, W., Zhang, X. and Svenningsson, P. (2022) Prosaposin Reduces α-Synuclein in Cells and Saposin C Dislodges It from Glucosylceramide-Enriched Lipid Membranes. Journal of Molecular Neuroscience, 72, 2313-2325. [Google Scholar] [CrossRef] [PubMed]
[38] Liu, B., Mosienko, V., Vaccari Cardoso, B., Prokudina, D., Huentelman, M., Teschemacher, A.G., et al. (2018) Glio‐ and Neuro‐Protection by Prosaposin Is Mediated by Orphan G‐Protein Coupled Receptors GPR37L1 and GPR37. Glia, 66, 2414-2426. [Google Scholar] [CrossRef] [PubMed]
[39] Ma, Q., Tian, J., Lou, Y., Guo, R., Ma, X., Wu, J., et al. (2025) Oligodendrocytes Drive Neuroinflammation and Neurodegeneration in Parkinson’s Disease via the Prosaposin-GPR37-IL-6 Axis. Cell Reports, 44, Article ID: 115266. [Google Scholar] [CrossRef] [PubMed]
[40] Misasi, R., Garofalo, T., Di Marzio, L., Mattei, V., Gizzi, C., Hiraiwa, M., et al. (2004) Prosaposin: A New Player in Cell Death Prevention of U937 Monocytic Cells. Experimental Cell Research, 298, 38-47. [Google Scholar] [CrossRef] [PubMed]
[41] Foltynie, T., Bruno, V., Fox, S., Kühn, A.A., Lindop, F. and Lees, A.J. (2024) Medical, Surgical, and Physical Treatments for Parkinson’s Disease. The Lancet, 403, 305-324. [Google Scholar] [CrossRef] [PubMed]
[42] Vijiaratnam, N., Simuni, T., Bandmann, O., Morris, H.R. and Foltynie, T. (2021) Progress Towards Therapies for Disease Modification in Parkinson’s Disease. The Lancet Neurology, 20, 559-572. [Google Scholar] [CrossRef] [PubMed]
[43] Ambrosi, G., Ghezzi, C., Zangaglia, R., Levandis, G., Pacchetti, C. and Blandini, F. (2015) Ambroxol-Induced Rescue of Defective Glucocerebrosidase Is Associated with Increased LIMP-2 and Saposin C Levels in GBA1 Mutant Parkinson’s Disease Cells. Neurobiology of Disease, 82, 235-242. [Google Scholar] [CrossRef] [PubMed]

为你推荐