Neuroregeneration Research Institute, McLean Hospital/Harvard Medical School, Boston, USA.
Present Address: Department of Biochemistry, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, 31096, Haifa, Israel.
J Neuroinflammation. 2019 Jul 22;16(1):153. doi: 10.1186/s12974-019-1532-2.
This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related disorders, age- and dose-dependent changes in glycolipid cell metabolism can lead to Parkinson's disease and related dementias. Recent results show that perturbation of sphingolipid metabolism can precede or is a part of abnormal protein handling in both genetic and idiopathic Parkinson's disease and Lewy body dementia. In aging and genetic predisposition with lipid disturbance, α-synuclein's normal vesicular and synaptic role may be detrimentally shifted toward accommodating and binding such lipids. Specific neuronal glycolipid, protein, and vesicular interactions create potential pathophysiology that is amplified by astroglial and microglial immune mechanisms resulting in neurodegeneration. This perspective provides a new logic for therapeutic interventions that do not focus on protein aggregation, but rather provides a guide to the complex biology and the common sequence of events that lead to age-dependent neurodegenerative disorders.
本文描述了在神经退行性疾病中导致细胞功能障碍和突触丧失的致病概念和因素，特别是糖脂异常。通过模拟溶酶体贮积症，如 Gaucher 病和相关疾病，糖脂细胞代谢的年龄和剂量依赖性变化可导致帕金森病和相关痴呆。最近的研究结果表明，鞘脂代谢的紊乱可能先于遗传和特发性帕金森病及路易体痴呆中异常蛋白处理，或者是其一部分。在脂质紊乱的老化和遗传易感性中，α-突触核蛋白的正常囊泡和突触作用可能会不利地转向容纳和结合这些脂质。特定神经元糖脂、蛋白和囊泡的相互作用产生了潜在的病理生理学，这种病理生理学被星形胶质细胞和小胶质细胞免疫机制放大，导致神经退行性变。这种观点为治疗干预提供了新的逻辑，这些治疗干预不专注于蛋白聚集，而是为复杂的生物学和导致与年龄相关的神经退行性疾病的常见事件序列提供了指导。
