SMPD1基因与帕金森病研究进展
Research Progress on the SMPD1 Gene and Parkinson’s Disease
DOI: 10.12677/acm.2026.161179, PDF,   
作者: 刘亦男, 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；SMPD1；酸性鞘磷脂酶；基本功能；发病机制；Parkinson’s Disease； SMPD1； Acid Sphingomyelinase； Basic Function； Pathogenesis
摘要: 帕金森病是一种常见的神经退行性疾病，主要的运动症状包括运动迟缓、震颤、肌肉强直、姿势不稳，非运动症状包括睡眠障碍、嗅觉减退、自主神经功能障碍和焦虑抑郁等，其病因和发病机制尚不明确，涉及多个方面。近年来，尼曼匹克病的主要致病基因——SMPD1基因，该基因编码酸性鞘磷脂酶，在维持脂质代谢方面发挥重要作用，被证明与PD的发病密切相关，本综述着重阐述SMPD1基因结构及基本功能、流行病学、导致PD发生发展的作用机制等。
Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder. Its major motor symptoms include bradykinesia, tremor, muscular rigidity, and postural instability, while non-motor symptoms include sleep disturbances, hyposmia, autonomic dysfunction, and anxiety or depression. The etiology and pathogenesis of PD remain unclear and involve multiple factors. In recent years, the primary pathogenic gene of Niemann-Pick disease—SMPD1, which encodes acid sphingomyelinase and plays an important role in lipid metabolism—has been shown to be closely associated with the onset of PD. This review focuses on the structure and basic functions of the SMPD1 gene, epidemiological findings, and its mechanisms contributing to the development and progression of PD.
文章引用：刘亦男, 武衡. SMPD1基因与帕金森病研究进展[J]. 临床医学进展, 2026, 16(1): 1390-1396. https://doi.org/10.12677/acm.2026.161179

参考文献

[1] Miller, D.B. and O’Callaghan, J.P. (2015) Biomarkers of Parkinson’s Disease: Present and Future. Metabolism, 64, S40-S46. [Google Scholar] [CrossRef] [PubMed]
[2] Goyal, V. and Radhakrishnan, D. (2018) Parkinson’s Disease: A Review. Neurology India, 66, 26-35. [Google Scholar] [CrossRef] [PubMed]
[3] Yahya, V., Di Fonzo, A. and Monfrini, E. (2023) Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview. International Journal of Molecular Sciences, 24, Article 6338. [Google Scholar] [CrossRef] [PubMed]
[4] Wang, R., Qin, Z., Huang, L., Luo, H., Peng, H., Zhou, X., et al. (2023) SMPD1 Expression Profile and Mutation Landscape Help Decipher Genotype-Phenotype Association and Precision Diagnosis for Acid Sphingomyelinase Deficiency. Hereditas, 160, Article No. 11. [Google Scholar] [CrossRef] [PubMed]
[5] Breiden, B. and Sandhoff, K. (2021) Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism. International Journal of Molecular Sciences, 22, Article 9001. [Google Scholar] [CrossRef] [PubMed]
[6] Kumar, M., Aguiar, M., Jessel, A., Thurberg, B.L., Underhill, L., Wong, H., et al. (2024) The Impact of Sphingomyelin on the Pathophysiology and Treatment Response to Olipudase Alfa in Acid Sphingomyelinase Deficiency. Genetics in Medicine Open, 2, Article 101888. [Google Scholar] [CrossRef] [PubMed]
[7] Kho, A.R., Choi, B.Y., Lee, S.H., Hong, D.K., Kang, B.S., Lee, S.H., et al. (2022) Administration of an Acidic Sphingomyelinase (Asmase) Inhibitor, Imipramine, Reduces Hypoglycemia-Induced Hippocampal Neuronal Death. Cells, 11, Article 667. [Google Scholar] [CrossRef] [PubMed]
[8] Kobayashi, T. (2023) Mapping Trasmembrane Distribution of Sphingomyelin. Emerging Topics in Life Sciences, 7, 31-45. [Google Scholar] [CrossRef] [PubMed]
[9] Young, M.M., Kester, M. and Wang, H. (2013) Sphingolipids: Regulators of Crosstalk between Apoptosis and Autophagy. Journal of Lipid Research, 54, 5-19. [Google Scholar] [CrossRef] [PubMed]
[10] Rhein, C., Zoicas, I., Marx, L.M., Zeitler, S., Hepp, T., von Zimmermann, C., et al. (2021) mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases Upon Antidepressant Treatment. International Journal of Molecular Sciences, 22, Article 5700. [Google Scholar] [CrossRef] [PubMed]
[11] Qing, Y., Guo, Y., Zhao, Q., Hu, P., Li, H., Yu, X., et al. (2023) Targeting Lysosomal HSP70 Induces Acid Sphingomyelinase‐Mediated Disturbance of Lipid Metabolism and Leads to Cell Death in T Cell Malignancies. Clinical and Translational Medicine, 13, e1229. [Google Scholar] [CrossRef] [PubMed]
[12] Ventura, A.E., Mestre, B. and Silva, L.C. (2019) Ceramide Domains in Health and Disease: A Biophysical Perspective. In: Advances in Experimental Medicine and Biology, Springer International Publishing, 79-108. [Google Scholar] [CrossRef] [PubMed]
[13] Perrotta, C., Cervia, D., De Palma, C., Assi, E., Pellegrino, P., Bassi, M.T., et al. (2015) The Emerging Role of Acid Sphingomyelinase in Autophagy. Apoptosis, 20, 635-644. [Google Scholar] [CrossRef] [PubMed]
[14] Ghandour, B., Dbaibo, G. and Darwiche, N. (2021) The Unfolding Role of Ceramide in Coordinating Retinoid-Based Cancer Therapy. Biochemical Journal, 478, 3621-3642. [Google Scholar] [CrossRef] [PubMed]
[15] Choi, B.J., Park, M.H., Jin, H.K. and Bae, J. (2024) Acid Sphingomyelinase as a Pathological and Therapeutic Target in Neurological Disorders: Focus on Alzheimer’s Disease. Experimental & Molecular Medicine, 56, 301-310. [Google Scholar] [CrossRef] [PubMed]
[16] Pfrieger, F.W. (2023) The Niemann-Pick Type Diseases—A Synopsis of Inborn Errors in Sphingolipid and Cholesterol Metabolism. Progress in Lipid Research, 90, Article 101225. [Google Scholar] [CrossRef] [PubMed]
[17] Dagan, E., Adir, V., Schlesinger, I., Borochowitz, Z., Ayoub, M., Mory, A., et al. (2015) SMPD1 Mutations and Parkinson Disease. Parkinsonism & Related Disorders, 21, 1296-1297. [Google Scholar] [CrossRef] [PubMed]
[18] Foo, J., Liany, H., Bei, J., Yu, X., Liu, J., Au, W., et al. (2013) A Rare Lysosomal Enzyme Gene SMPD1 Variant (p.r591c) Associates with Parkinson’s Disease. Neurobiology of Aging, 34, 2890.e13-2890.e15. [Google Scholar] [CrossRef] [PubMed]
[19] Macauley, S.L., Sidman, R.L., Schuchman, E.H., Taksir, T. and Stewart, G.R. (2008) Neuropathology of the Acid Sphingomyelinase Knockout Mouse Model of Niemann-Pick a Disease Including Structure-Function Studies Associated with Cerebellar Purkinje Cell Degeneration. Experimental Neurology, 214, 181-192. [Google Scholar] [CrossRef] [PubMed]
[20] Alecu, I. and Bennett, S.A.L. (2019) Dysregulated Lipid Metabolism and Its Role in Α-Synucleinopathy in Parkinson’s Disease. Frontiers in Neuroscience, 13, Article ID: 328. [Google Scholar] [CrossRef] [PubMed]
[21] Galper, J., Dean, N.J., Pickford, R., Lewis, S.J.G., Halliday, G.M., Kim, W.S., et al. (2022) Lipid Pathway Dysfunction Is Prevalent in Patients with Parkinson’s Disease. Brain, 145, 3472-3487. [Google Scholar] [CrossRef] [PubMed]
[22] Galvagnion, C. (2017) The Role of Lipids Interacting with Α-Synuclein in the Pathogenesis of Parkinson’s Disease. Journal of Parkinson’s Disease, 7, 433-450. [Google Scholar] [CrossRef] [PubMed]
[23] Moors, T., Paciotti, S., Chiasserini, D., Calabresi, P., Parnetti, L., Beccari, T., et al. (2016) Lysosomal Dysfunction and Α‐synuclein Aggregation in Parkinson’s Disease: Diagnostic Links. Movement Disorders, 31, 791-801. [Google Scholar] [CrossRef] [PubMed]
[24] Yuyama, K., Sun, H., Mitsutake, S. and Igarashi, Y. (2012) Sphingolipid-Modulated Exosome Secretion Promotes Clearance of Amyloid-β by Microglia. Journal of Biological Chemistry, 287, 10977-10989. [Google Scholar] [CrossRef] [PubMed]
[25] Théry, C., Witwer, K.W., Aikawa, E., Alcaraz, M.J., Anderson, J.D., Andriantsitohaina, R., et al. (2018) Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018): A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines. Journal of Extracellular Vesicles, 7, Article 1535750. [Google Scholar] [CrossRef] [PubMed]
[26] Krylova, S.V. and Feng, D. (2023) The Machinery of Exosomes: Biogenesis, Release, and Uptake. International Journal of Molecular Sciences, 24, Article 1337. [Google Scholar] [CrossRef] [PubMed]
[27] Kurzawa-Akanbi, M., Tammireddy, S., Fabrik, I., Gliaudelytė, L., Doherty, M.K., Heap, R., et al. (2021) Altered Ceramide Metabolism Is a Feature in the Extracellular Vesicle-Mediated Spread of Alpha-Synuclein in Lewy Body Disorders. Acta Neuropathologica, 142, 961-984. [Google Scholar] [CrossRef] [PubMed]
[28] Mc Donald, J.M. and Krainc, D. (2017) Lysosomal Proteins as a Therapeutic Target in Neurodegeneration. Annual Review of Medicine, 68, 445-458. [Google Scholar] [CrossRef] [PubMed]
[29] Bellomo, G., Paciotti, S., Gatticchi, L. and Parnetti, L. (2020) The Vicious Cycle between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction. Movement Disorders, 35, 34-44. [Google Scholar] [CrossRef] [PubMed]
[30] Schuchman, E.H. (2010) Acid Sphingomyelinase, Cell Membranes and Human Disease: Lessons from Niemann-Pick Disease. FEBS Letters, 584, 1895-1900. [Google Scholar] [CrossRef] [PubMed]
[31] Corcelle-Termeau, E., Vindeløv, S.D., Hämälistö, S., Mograbi, B., Keldsbo, A., Bräsen, J.H., et al. (2016) Excess Sphingomyelin Disturbs ATG9A Trafficking and Autophagosome Closure. Autophagy, 12, 833-849. [Google Scholar] [CrossRef] [PubMed]
[32] Medina, D.L., Di Paola, S., Peluso, I., Armani, A., De Stefani, D., Venditti, R., et al. (2015) Lysosomal Calcium Signalling Regulates Autophagy through Calcineurin and TFEB. Nature Cell Biology, 17, 288-299. [Google Scholar] [CrossRef] [PubMed]
[33] Settembre, C. and Medina, D.L. (2015) TFEB and the CLEAR Network. In: Methods in Cell Biology, Elsevier, 45-62. [Google Scholar] [CrossRef] [PubMed]
[34] Carsana, E.V., Lunghi, G., Prioni, S., Mauri, L., Loberto, N., Prinetti, A., et al. (2022) Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A. Journal of Molecular Neuroscience, 72, 1482-1499. [Google Scholar] [CrossRef] [PubMed]
[35] Pajares, M., I. Rojo, A., Manda, G., Boscá, L. and Cuadrado, A. (2020) Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. Cells, 9, Article 1687. [Google Scholar] [CrossRef] [PubMed]
[36] Chung, C.Y., Koprich, J.B., Siddiqi, H. and Isacson, O. (2009) Dynamic Changes in Presynaptic and Axonal Transport Proteins Combined with Striatal Neuroinflammation Precede Dopaminergic Neuronal Loss in a Rat Model of AAV Α-synucleinopathy. The Journal of Neuroscience, 29, 3365-3373. [Google Scholar] [CrossRef] [PubMed]
[37] Norris, G. and Blesso, C. (2017) Dietary and Endogenous Sphingolipid Metabolism in Chronic Inflammation. Nutrients, 9, Article 1180. [Google Scholar] [CrossRef] [PubMed]
[38] Pant, D.C., Aguilera-Albesa, S. and Pujol, A. (2020) Ceramide Signalling in Inherited and Multifactorial Brain Metabolic Diseases. Neurobiology of Disease, 143, Article 105014. [Google Scholar] [CrossRef] [PubMed]
[39] Hallett, P.J., Engelender, S. and Isacson, O. (2019) Lipid and Immune Abnormalities Causing Age-Dependent Neurodegeneration and Parkinson’s Disease. Journal of Neuroinflammation, 16, Article No. 153. [Google Scholar] [CrossRef] [PubMed]
[40] Qin, J., Ma, Z., Chen, X. and Shu, S. (2023) Microglia Activation in Central Nervous System Disorders: A Review of Recent Mechanistic Investigations and Development Efforts. Frontiers in Neurology, 14, Article ID: 1103416. [Google Scholar] [CrossRef] [PubMed]
[41] Flores-Leon, M. and Outeiro, T.F. (2023) More than Meets the Eye in Parkinson’s Disease and Other Synucleinopathies: From Proteinopathy to Lipidopathy. Acta Neuropathologica, 146, 369-385. [Google Scholar] [CrossRef] [PubMed]
[42] Estes, R.E., Lin, B., Khera, A. and Davis, M.Y. (2021) Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo? Frontiers in Molecular Neuroscience, 14, Article ID: 788695. [Google Scholar] [CrossRef] [PubMed]
[43] Trist, B.G., Hare, D.J. and Double, K.L. (2019) Oxidative Stress in the Aging Substantia Nigra and the Etiology of Parkinson’s Disease. Aging Cell, 18, e13031. [Google Scholar] [CrossRef] [PubMed]
[44] Chen, Q., Kovilakath, A., Allegood, J., Thompson, J., Hu, Y., Cowart, L.A., et al. (2023) Endoplasmic Reticulum Stress and Mitochondrial Dysfunction during Aging: Role of Sphingolipids. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids, 1868, Article 159366. [Google Scholar] [CrossRef] [PubMed]
[45] Zhang, S., He, Y., Sen, B. and Wang, G. (2020) Reactive Oxygen Species and Their Applications toward Enhanced Lipid Accumulation in Oleaginous Microorganisms. Bioresource Technology, 307, Article 123234. [Google Scholar] [CrossRef] [PubMed]

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