Section of Biochemistry, Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
Mol Neurobiol. 2010 Jun;41(2-3):314-40. doi: 10.1007/s12035-009-8096-6. Epub 2010 Feb 3.
Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron-glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid-protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid beta peptide in Alzheimer's disease, huntingtin in Huntington's disease, alpha-synuclein in Parkinson's disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.
鞘脂是真核细胞膜中作为少量成分存在的极性膜脂。鞘脂在神经细胞中高度富集，在那里它们发挥着重要的生物学功能。它们深刻地影响细胞膜的结构和几何性质以及侧向有序性，调节几种膜相关蛋白的功能，并产生重要的细胞内和细胞外脂质介质。鞘脂代谢沿着神经系统的分化和发育进行调节，表达一种特殊的时空调节的鞘脂模式对于维持神经系统的功能完整性是必不可少的：神经系统中的鞘脂参与控制神经元存活、迁移和分化、对营养因子的反应性、突触稳定性和突触传递以及神经元-胶质相互作用的几种信号通路，包括中枢和周围髓鞘的形成和稳定性。在几种神经退行性疾病中，鞘脂代谢被深度失调，导致异常的鞘脂模式和改变的膜组织的表达，这些表达参与了这些疾病发病机制相关的几种事件。这种失调的最令人印象深刻的后果是异常的鞘脂-蛋白相互作用，这些相互作用至少部分是导致疾病特异性蛋白同工型错误折叠事件的原因，例如阿尔茨海默病中的淀粉样β肽、亨廷顿病中的亨廷顿蛋白、帕金森病中的α-突触核蛋白和传染性脑病中的朊病毒。靶向鞘脂代谢是设计针对这些疾病的新型治疗策略的一个未充分利用但现实的机会。
