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    The roles of prosaposin in neurological disorders: current understandings and prospects

    • Jingying Li
    • Chunyuan Li


    Abstract

    Prosaposin is a multifunctional protein known for its regulatory role in lysosomal physiological functions and its involvement as a secreted protein in various physiological processes. It has been identified as a factor in several major neurological disorders, including Parkinson's Disease (PD), Alzheimer's disease (AD), Frontotemporal dementia (FTD), schizophrenia, and nerve injury. A comprehensive understanding of prosaposin's involvement in the pathological processes of these diseases and exploring their commonalities among different diseases could shed light on new strategies for understanding the mechanisms and treating various neurological disorders. This review summarizes the role of prosaposin in the pathogenesis of multiple neurological diseases and discusses its commonalities across these diseases, offering an outlook on future research directions regarding the diagnosis and treatment.

    Keywords: Prosaposin Saposin Neurodegenerative disease Neuropsychiatric disorders Lysosome
    Section

    References

    1. Ahn, V. E., Faull, K. F., Whitelegge, J. P., Fluharty, A. L., & Privé, G. G. (2002). Crystal Structure of Saposin B Reveals a Dimeric Shell for Lipid Binding. Proceedings of the National Academy of Sciences. doi:10.1073/pnas.0136947100
    2. Bang, J., Spina, S., & Miller, B. L. (2015). Frontotemporal Dementia. The Lancet. doi:10.1016/s0140-6736(15)00461-4
    3. Bellomo, G., Paciotti, S., Gatticchi, L., & Parnetti, L. (2020). The vicious cycle between alpha-synuclein aggregation and autophagic-lysosomal dysfunction. Mov Disord, 35(1), 34-44. doi:10.1002/mds.27895
    4. Champagne, M.-J., Lamontagne, S., & Potier, M. (1994). Binding of GM1‐ganglioside to a Synthetic Peptide Derived From the Lysosomal Sphingolipid‐activator‐protein Saposin B. Febs Letters. doi:10.1016/0014-5793(94)00536-2
    5. Corti, R., Cox, A., Cassina, V., Nardo, L., Salerno, D., Marrano, C. A., . . . Mantegazza, F. (2020). The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation. International Journal of Molecular Sciences. doi:10.3390/ijms21031066
    6. Decressac, M., Mattsson, B., Weikop, P., Lundblad, M., Jakobsson, J., & Björklund, A. (2013). TFEB-mediated Autophagy Rescues Midbrain Dopamine Neurons From Α-Synuclein Toxicity. Proceedings of the National Academy of Sciences. doi:10.1073/pnas.1305623110
    7. Do, J., McKinney, C. E., Sharma, P., & Sidransky, E. (2019). Glucocerebrosidase and Its Relevance to Parkinson Disease. Molecular Neurodegeneration. doi:10.1186/s13024-019-0336-2
    8. Feng, R., Muraleedharan Saraswathy, V., Mokalled, M. H., & Cavalli, V. (2023). Self-renewing macrophages in dorsal root ganglia contribute to promote nerve regeneration. Proc Natl Acad Sci U S A, 120(7), e2215906120. doi:10.1073/pnas.2215906120
    9. Forrest, S. L., Crockford, D. R., Sizemova, A., McCann, H., Shepherd, C. E., McGeachie, A. B., . . . Halliday, G. M. (2019). Coexisting Lewy body disease and clinical parkinsonism in frontotemporal lobar degeneration. Neurology, 92(21), e2472-e2482. doi:10.1212/wnl.0000000000007530
    10. Freeman, D. W., Cedillos, R. O., Choyke, S., Lukic, Z., McGuire, K. A., Marvin, S. A., . . . Campbell, E. M. (2013). Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis. PLoS One. doi:10.1371/journal.pone.0062143
    11. Giddens, M. M., Wong, J. C., Schroeder, J. P., Farrow, E. G., Smith, B. M., Owino, S., . . . LePichon, J.-B. (2017). GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant. Neurobiology of Disease, 106, 181-190.
    12. Greene, N. D., & Copp, A. J. (2014). Neural tube defects. Annu Rev Neurosci, 37, 221-242. doi:10.1146/annurev-neuro-062012-170354
    13. Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K. W., Takeda, S., Banerji, A. O., . . . Hyman, B. T. (2012). Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid Β Peptide. Journal of Neuroscience. doi:10.1523/jneurosci.1542-12.2012
    14. He, Y., Kaya, I., Shariatgorji, R., Lundkvist, J., Wahlberg, L. U., Nilsson, A., . . . Svenningsson, P. (2023). Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents. Nature Communications, 14(1). doi:10.1038/s41467-023-41539-5
    15. He, Y. C., Zhang, X. Q., Flais, I., & Svenningsson, P. (2022). Decreased Prosaposin and Progranulin in the Cingulate Cortex Are Associated with Schizophrenia Pathophysiology. International Journal of Molecular Sciences, 23(19). doi:ARTN 12056 10.3390/ijms231912056
    16. Hindle, S. J., Hebbar, S., Schwudke, D., Elliott, C. J. H., & Sweeney, S. T. (2017). A Saposin Deficiency Model in Drosophila : Lysosomal Storage, Progressive Neurodegeneration and Sensory Physiological Decline. Neurobiology of Disease. doi:10.1016/j.nbd.2016.11.012
    17. Jiang, Y., Zhou, J., Hou, D., Luo, P., Gao, H., Ma, Y., . . . Zhang, Y. (2019). Prosaposin Is a Biomarker of Mesenchymal Glioblastoma and Regulates Mesenchymal Transition Through the TGF‐β1/Smad Signaling Pathway. The Journal of Pathology. doi:10.1002/path.5278
    18. Khan, S., Takeuchi, A., Nabeka, H., Khan, F., Shimokawa, T., Takanezawa, S., . . . Matsuda, S. (2023). Administration of prosaposin-derived neurotrophic factor to neural tube defects facilitates regeneration and restores neurological functions. iScience, 26(4), 106277. doi:10.1016/j.isci.2023.106277
    19. Kim, M. J., Jeong, H., & Krainc, D. (2022). Lysosomal ceramides regulate cathepsin B-mediated processing of saposin C and glucocerebrosidase activity. Hum Mol Genet, 31(14), 2424-2437. doi:10.1093/hmg/ddac047
    20. Kojima, R., Zurbruegg, M., Li, T., Paslawski, W., Zhang, X., & Svenningsson, P. (2022). Prosaposin Reduces alpha-Synuclein in Cells and Saposin C Dislodges it from Glucosylceramide-enriched Lipid Membranes. J Mol Neurosci, 72(11), 2313-2325. doi:10.1007/s12031-022-02066-y
    21. Kotani, Y., Matsuda, S., Wen, T. C., Sakanaka, M., Tanaka, J., Maeda, N., . . . Sano, A. (1996). A hydrophilic peptide comprising 18 amino acid residues of the prosaposin sequence has neurotrophic activity in vitro and in vivo. Journal of Neurochemistry, 66(5), 2197-2200.
    22. Kuusimäki, T., Al‐Abdulrasul, H., Kurki, S., Hietala, J., Hartikainen, S., Koponen, M., . . . Kaasinen, V. (2021). Increased risk of Parkinson's disease in patients with schizophrenia spectrum disorders. Movement Disorders, 36(6), 1353-1361.
    23. Lin, H.-L., Lin, H.-C., & Chen, Y.-H. (2014). Psychiatric diseases predated the occurrence of Parkinson disease: a retrospective cohort study. Annals of Epidemiology, 24(3), 206-213.
    24. Lin, Z. H., & Zhang, B. R. (2021). Striking while the iron is hot: the role of Prosaposin (PSAP) in Parkinson's disease. Movement Disorders, 36(10), 2224-2224.
    25. Liu, B., Mosienko, V., Vaccari Cardoso, B., Prokudina, D., Huentelman, M., Teschemacher, A. G., & Kasparov, S. (2018). Glio- and neuro-protection by prosaposin is mediated by orphan G-protein coupled receptors GPR37L1 and GPR37. Glia, 66(11), 2414-2426. doi:10.1002/glia.23480
    26. Luk, K. C., Kehm, V., Carroll, J. C., Zhang, B., O’Brien, P. K. H., Trojanowski, J. Q., & Lee, V. M. Y. (2012). Pathological Α-Synuclein Transmission Initiates Parkinson-Like Neurodegeneration in Nontransgenic Mice. Science. doi:10.1126/science.1227157
    27. Luo, D., Li, J., Liu, H., Wang, J., Xia, Y., Qiu, W., . . . Ge, W. (2023). Integrative Transcriptomic Analyses of Hippocampal-Entorhinal System Subfields Identify Key Regulators in Alzheimer's Disease. Adv Sci (Weinh), 10(22), e2300876. doi:10.1002/advs.202300876
    28. Martin-Bastida, A., Ward, R. J., Newbould, R., Piccini, P., Sharp, D., Kabba, C., . . . Tricta, F. (2017). Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Scientific reports, 7(1), 1398.
    29. Mendsaikhan, A., Tooyama, I., Bellier, J. P., Serrano, G. E., Sue, L. I., Lue, L. F., . . . Walker, D. G. (2019). Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer's disease and aged brains: increased levels correlate with neuropathology. Acta Neuropathol Commun, 7(1), 215. doi:10.1186/s40478-019-0862-8
    30. Mendsaikhan, A., Tooyama, I., Serrano, G. E., Beach, T. G., & Walker, D. G. (2021). Loss of Lysosomal Proteins Progranulin and Prosaposin Associated with Increased Neurofibrillary Tangle Development in Alzheimer Disease. J Neuropathol Exp Neurol, 80(8), 741-753. doi:10.1093/jnen/nlab056
    31. Menozzi, E., & Schapira, A. H. V. (2020). Enhancing the Activity of Glucocerebrosidase as a Treatment for Parkinson Disease. CNS Drugs. doi:10.1007/s40263-020-00746-0
    32. Meyer, R. C., Giddens, M. M., Coleman, B. M., & Hall, R. A. (2014). The protective role of prosaposin and its receptors in the nervous system. Brain Research, 1585, 1-12.
    33. Morimoto, S., Yamamoto, Y., O’Brien, J. S., & Kishimoto, Y. (1990). Distribution of Saposin Proteins (Sphingolipid Activator Proteins) in Lysosomal Storage and Other Diseases. Proceedings of the National Academy of Sciences. doi:10.1073/pnas.87.9.3493
    34. Nabeka, H. (2021). Prosaposin, a neurotrophic factor, protects neurons against kainic acid-induced neurotoxicity. Anatomical Science International, 96(3), 359-369.
    35. Oji, Y., Hatano, T., Ueno, S. I., Funayama, M., Ishikawa, K. I., Okuzumi, A., . . . Hattori, N. (2020). Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain, 143(4), 1190-1205. doi:10.1093/brain/awaa064
    36. Qi, X., Kondoh, K., Krusling, D., Kelso, G. J., Leonova, T., & Grabowski, G. A. (1999). Conformational and Amino Acid Residue Requirements for the Saposin C Neuritogenic Effect. Biochemistry. doi:10.1021/bi990079o
    37. Qiu, X., Guo, Y., Liu, M. F., Zhang, B., Li, J., Wei, J. F., & Li, M. (2023). Single-cell RNA-sequencing analysis reveals enhanced non-canonical neurotrophic factor signaling in the subacute phase of traumatic brain injury. CNS Neurosci Ther, 29(11), 3446-3459. doi:10.1111/cns.14278
    38. Ross, C. A., Margolis, R. L., Reading, S., Pletnikov, M. V., & Coyle, J. T. (2006). Neurobiology of Schizophrenia. Neuron. doi:10.1016/j.neuron.2006.09.015
    39. Ruz, C., Barrero, F. J., Pelegrina, J., Bandrés-Ciga, S., Vives, F., & Duran, R. (2022). Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome. International Journal of Molecular Sciences, 23(19). doi:ARTN 12004
    40. 3390/ijms231912004
    41. Schapira, A. H., Chaudhuri, K. R., & Jenner, P. (2017). Non-motor features of Parkinson disease. Nature Reviews Neuroscience, 18(7), 435-450.
    42. Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chetelat, G., Teunissen, C. E., . . . van der Flier, W. M. (2021). Alzheimer's disease. Lancet, 397(10284), 1577-1590. doi:10.1016/S0140-6736(20)32205-4
    43. Sephton, C. F., Cenik, B. K., Herz, J., & Yu, G. (2012). Progranulin: A Proteolytically Processed Protein at the Crossroads of Inflammation and Neurodegeneration. Journal of Biological Chemistry. doi:10.1074/jbc.r112.399170
    44. Sharoar, M. G., Palko, S., Ge, Y., Saido, T. C., & Yan, R. (2021). Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer's disease brains. Mol Neurodegener, 16(1), 45. doi:10.1186/s13024-021-00464-1
    45. Shrivastava, A., Sousa, A. D., & Rao, G. (2016). Brain-Derived Neurotrophic Factor and Suicide in Schizophrenia: Critical Role of Neuroprotective Mechanisms as an Emerging Hypothesis. Indian Journal of Psychological Medicine. doi:10.4103/0253-7176.194913
    46. Simon, M. J., Logan, T., DeVos, S. L., & Di Paolo, G. (2023). Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia. Trends Cell Biol, 33(4), 324-339. doi:10.1016/j.tcb.2022.09.006
    47. Smeland, O. B., Shadrin, A., Bahrami, S., Broce, I., Tesli, M., Frei, O., . . . Bettella, F. (2021). Genome-wide association analysis of Parkinson’s disease and schizophrenia reveals shared genetic architecture and identifies novel risk loci. Biological Psychiatry, 89(3), 227-235.
    48. Sun, Y., Ran, H., Zamzow, M., Kitatani, K., Skelton, M. R., Williams, M. T., . . . Grabowski, G. A. (2009). Specific Saposin C Deficiency: CNS Impairment and Acid -Glucosidase Effects in the Mouse. Human Molecular Genetics. doi:10.1093/hmg/ddp531
    49. Sun, Y., Witte, D. P., Ran, H., Zamzow, M., Barnes, S., Cheng, H., . . . Grabowski, G. A. (2008). Neurological Deficits and Glycosphingolipid Accumulation in Saposin B Deficient Mice. Human Molecular Genetics. doi:10.1093/hmg/ddn135
    50. Sun, Y., Zamzow, M., Ran, H., Zhang, W., Quinn, B., Barnes, S., . . . Grabowski, G. A. (2013). Tissue-Specific Effects of Saposin a and Saposin B on Glycosphingolipid Degradation in Mutant Mice. Human Molecular Genetics. doi:10.1093/hmg/ddt096
    51. Swift, I. J., Sogorb‐Esteve, A., Heller, C., Synofzik, M., Otto, M., Graff, C., . . . Rohrer, J. D. (2020). Fluid Biomarkers in Frontotemporal Dementia: Past, Present and Future. Journal of Neurology Neurosurgery & Psychiatry. doi:10.1136/jnnp-2020-323520
    52. Takahashi, H., Bhagwagar, S., Nies, S. H., Chiasseu, M. T., Wang, G., Mackenzie, I. R., & Strittmatter, S. M. (2022). Reduced progranulin increases tau and alpha-synuclein inclusions and alters phenotypes of tauopathy mice via glucocerebrosidase. bioRxiv, 2022.2012. 2025.521308.
    53. Takahashi, T., Suzuki, M., Kawasaki, Y., Hagino, H., Yamashita, I., Nohara, S., . . . Kurachi, M. (2003). Perigenual cingulate gyrus volume in patients with schizophrenia: a magnetic resonance imaging study. Biological Psychiatry, 53(7), 593-600. doi:10.1016/s0006-3223(02)01483-x
    54. Tamargo, R. J., Velayati, A., Goldin, E., & Sidransky, E. (2012). The role of saposin C in Gaucher disease. Mol Genet Metab, 106(3), 257-263. doi:10.1016/j.ymgme.2012.04.024
    55. Taniguchi, M., Nabeka, H., Yamamiya, K., Khan, M. S. I., Shimokawa, T., Islam, F., . . . Matsuda, S. (2021). The expression of prosaposin and its receptors, GRP37 and GPR37L1, are increased in the developing dorsal root ganglion. PLoS One, 16(8), e0255958. doi:10.1371/journal.pone.0255958
    56. Tian, R., Abarientos, A., Hong, J., Hashemi, S. H., Yan, R., Drager, N., . . . Kampmann, M. (2021). Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis. Nat Neurosci, 24(7), 1020-1034. doi:10.1038/s41593-021-00862-0
    57. Valdez, C., Ysselstein, D., Young, T. J., Zheng, J., & Krainc, D. (2020). Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity. Hum Mol Genet, 29(5), 716-726. doi:10.1093/hmg/ddz229
    58. van Kruining, D., Luo, Q., van Echten-Deckert, G., Mielke, M. M., Bowman, A., Ellis, S., . . . Martinez-Martinez, P. (2020). Sphingolipids as prognostic biomarkers of neurodegeneration, neuroinflammation, and psychiatric diseases and their emerging role in lipidomic investigation methods. Advanced drug delivery reviews, 159, 232-244.
    59. van Leent, M. M. T., Beldman, T. J., Toner, Y. C., Lameijer, M. A., Rother, N., Bekkering, S., . . . Duivenvoorden, R. (2021). Prosaposin mediates inflammation in atherosclerosis. Sci Transl Med, 13(584). doi:10.1126/scitranslmed.abe1433
    60. Veenit, V., Zhang, X., Paslawski, W., Mantas, I., & Svenningsson, P. (2022). Impaired Aversive Memory Formation in GPR37L1KO Mice. International Journal of Molecular Sciences, 23(22), 14290.
    61. Weller, J., & Budson, A. (2018). Current understanding of Alzheimer’s disease diagnosis and treatment. F1000Research, 7.
    62. Wu, K. J., Hung, T. W., Wang, Y. S., Chen, Y. H., Bae, E. K., & Yu, S. J. (2023). Prosaposin PS18 reduces dopaminergic neurodegeneration in a 6-hydroxydopamine rat model of Parkinson's disease. Sci Rep, 13(1), 8148. doi:10.1038/s41598-023-35274-6
    63. Wu, Z., Li, G., Wang, S., Zhang, N., Li, X., Zhang, F., . . . Wang, Y. (2023). Single-cell analysis of spinal cord injury reveals functional heterogeneity of oligodendrocyte lineage cells. Gene, 886, 147713. doi:10.1016/j.gene.2023.147713
    64. Yap, T. L., Gruschus, J. M., Velayati, A., Sidransky, E., & Lee, J. C. (2013). Saposin C protects glucocerebrosidase against alpha-synuclein inhibition. Biochemistry, 52(41), 7161-7163. doi:10.1021/bi401191v
    65. Zhao, Q., & Morales, C. R. (2000). Identification of a Novel Sequence Involved in Lysosomal Sorting of the Sphingolipid Activator Protein Prosaposin. Journal of Biological Chemistry. doi:10.1074/jbc.m003497200

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    Li, Jingying, and Chunyuan Li. “The Roles of Prosaposin in Neurological Disorders: Current Understandings and Prospects ”. Human Brain, vol. 2, no. 3, Sept. 2023, doi:10.37819/hb.3.1781.
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    DOI: https://doi.org/10.37819/hb.3.1781

    Published: 2023-09-01

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