Motor neuron diseases (MNDs) encompass an extensive and heterogeneous group of upper and/or lower motor neuron degenerative disorders, in which the particular clinical outcomes stem from the specific neuronal component involved in each condition. While mutations in a large number of molecules associated with lipid metabolism are known to be implicated in MNDs, there remains a lack of clarity regarding the key functional pathways involved, and their inter-relationships. This review highlights evidence that defines defects within two specific lipid (cholesterol/oxysterol and phosphatidylethanolamine) biosynthetic cascades as being centrally involved in MND, particularly hereditary spastic paraplegia. We also identify how other MND-associated molecules may impact these cascades, in particular through impaired organellar interfacing, to propose 'subcellular lipidome imbalance' as a likely common pathomolecular theme in MND. Further exploration of this mechanism has the potential to identify new therapeutic targets and management strategies for modulation of disease progression in hereditary spastic paraplegias and other MNDs.

中文翻译：

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脂质代谢途径在运动神经元退行性疾病中汇聚。

运动神经元疾病 (MND) 包括一组广泛且异质的上运动神经元和/或下运动神经元退行性疾病，其中特定的临床结果源于每种病症所涉及的特定神经元成分。虽然已知与脂质代谢相关的大量分子的突变与 MND 有关联，但关于所涉及的关键功能途径及其相互关系仍缺乏明确性。本综述强调了将两种特定脂质（胆固醇/氧甾醇和磷脂酰乙醇胺）生物合成级联中的缺陷定义为 MND 中枢参与的证据，特别是遗传性痉挛性截瘫。我们还确定了其他 MND 相关分子如何影响这些级联反应，特别是通过受损的细胞器界面，提出“ 亚细胞脂质组失衡'可能是 MND 中常见的病理分子主题。对这种机制的进一步探索有可能确定新的治疗靶点和管理策略，以调节遗传性痉挛性截瘫和其他 MND 的疾病进展。