Unraveling Isoform Complexity: The Roles of M1‐ and M87‐Spastin in Spastic Paraplegia 4 (SPG4)

Abstract Spastic Paraplegia 4 (SPG4) is a debilitating neurodegenerative disorder characterized by progressive muscle weakness and spasticity in the lower limbs, often leading to gait impairment. Central to SPG4 pathology is the die‐back degeneration of corticospinal tracts, primarily driven by mutations in the spastin protein encoded by the SPAST gene. SPAST gives rise to two major spastin isoforms, M1‐ and M87‐spastin, 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‐ and M87‐spastin isoforms, highlighting their distinct and overlapping functions, and exploring their potential roles in the haploinsufficiency and gain‐of‐toxicity mechanisms underlying SPG4. We also present a novel perspective on the evolutionary emergence of M1‐spastin and its potential unique involvement in the pathogenesis of SPG4. Drawing upon the latest research, we propose an intriguing hypothesis regarding the hetero‐oligomerization of M1‐ and M87‐spastin, 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‐specific roles of spastin in SPG4, with the ultimate goal of advancing targeted treatments for this challenging neurodegenerative disorder. © 2024 International Parkinson and Movement Disorder Society.