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Central to SPG4 pathology is the die\u2010back degeneration of corticospinal tracts, primarily driven by mutations in the spastin protein encoded by the <jats:italic>SPAST<\/jats:italic> gene. <jats:italic>SPAST<\/jats:italic> gives rise to two major spastin isoforms, M1\u2010 and M87\u2010spastin, which are generated from distinct translation initiation sites. Although spastin is implicated in various cellular functions, the specific roles of each isoform in the pathogenesis of SPG4 remain poorly understood. This review offers an overview of the genetic and structural organization of the M1\u2010 and M87\u2010spastin isoforms, highlighting their distinct and overlapping functions, and exploring their potential roles in the haploinsufficiency and gain\u2010of\u2010toxicity mechanisms underlying SPG4. We also present a novel perspective on the evolutionary emergence of M1\u2010spastin and its potential unique involvement in the pathogenesis of SPG4. Drawing upon the latest research, we propose an intriguing hypothesis regarding the hetero\u2010oligomerization of M1\u2010 and M87\u2010spastin, exploring how their interaction may drive disease progression and open new avenues for therapeutic intervention. By integrating the current research with these fresh insights, we seek to illuminate the complex molecular mechanisms driving SPG4 and foster the development of innovative therapeutic strategies. This review not only incorporates existing knowledge but also lays the groundwork for future studies aimed at uncovering the isoform\u2010specific roles of spastin in SPG4, with the ultimate goal of advancing targeted treatments for this challenging neurodegenerative disorder. \u00a9 2024 International Parkinson and Movement Disorder Society.<\/jats:p>","DOI":"10.1002\/mds.30072","type":"journal-article","created":{"date-parts":[[2024,11,30]],"date-time":"2024-11-30T01:19:52Z","timestamp":1732929592000},"page":"420-430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Unraveling Isoform Complexity: The Roles of <scp>M1<\/scp>\u2010 and <scp>M87<\/scp>\u2010Spastin in Spastic Paraplegia 4 (<scp>SPG4<\/scp>)"],"prefix":"10.1002","volume":"40","author":[{"given":"Skandha","family":"Ramakrishnan","sequence":"first","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Mohan","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangji","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co\u2010innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co\u2010innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9896-602X","authenticated-orcid":false,"given":"Liang","family":"Qiang","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy Drexel University College of Medicine  Philadelphia Pennsylvania 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