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.

中文翻译：

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解开亚型复杂性：M1 和 M87 Spastin 在痉挛性截瘫 4 （SPG4） 中的作用


痉挛性截瘫 4 （SPG4） 是一种使人衰弱的神经退行性疾病，其特征是下肢进行性肌无力和痉挛状态，通常导致步态障碍。SPG4 病理学的核心是皮质脊髓束的死回变性，主要由 SPAST 基因编码的 spastin 蛋白突变驱动。SPAST 产生两种主要的 spastin 亚型，M1 和 M87 – spastin，它们由不同的翻译起始位点产生。尽管 spastin 与各种细胞功能有关，但每种亚型在 SPG4 发病机制中的特定作用仍然知之甚少。本综述概述了 M1 和 M87 spastin 亚型的遗传和结构组织，强调了它们独特和重叠的功能，并探讨了它们在 SPG4 的单倍体不足和毒性增益机制中的潜在作用。我们还提出了关于 M1-spastin 的进化出现及其在 SPG4 发病机制中的潜在独特参与的新观点。借鉴最新研究，我们提出了一个关于 M1 和 M87 异源寡聚化的有趣假设，探讨了它们的相互作用如何推动疾病进展并为治疗干预开辟新的途径。通过将当前研究与这些新见解相结合，我们寻求阐明驱动 SPG4 的复杂分子机制并促进创新治疗策略的发展。本综述不仅整合了现有知识，还为未来的研究奠定了基础，旨在揭示 spastin 在 SPG4 中的亚型特异性作用，最终目标是推进针对这种具有挑战性的神经退行性疾病的靶向治疗。 © 2024 年国际帕金森和运动障碍协会。