MUFA synthesis and stearoyl-CoA desaturase as a new pharmacological target for modulation of lipid and alpha-synuclein interaction against Parkinson's disease synucleinopathy

共核细胞病 神经保护 神经退行性变 α-突触核蛋白 帕金森病 神经科学 疾病 路易体 生物 药理学 医学 内科学
作者
Joanna Kula,Katarzyna Kuter
出处
期刊:Neuropharmacology [Elsevier]
卷期号:: 109865-109865 被引量:1
标识
DOI:10.1016/j.neuropharm.2024.109865
摘要

Protein pathology spreading within the nervous system, accompanies neurodegeneration and a spectrum of motor and cognitive dysfunctions. Currently available therapies against Parkinson's disease and other synucleinopathies are mostly symptomatic and fail to slow the disease progression in the long term. Modification of α synuclein (αS) aggregation and toxicity of its pathogenic forms is one of the main goals in neuroprotective approach. Since the discovery of lipid component of Lewy bodies fatty acids became a crucial, yet little explored target for research. MUFAs (monounsaturated fatty acids) are substrates for lipids, such as phospholipids, triglycerides and cholesteryl esters. They regulate membrane fluidity, take part in signal transduction, cellular differentiation and other fundamental processes. αS and MUFA interactions are essential for Lewy body pathology. αS increases level of MUFAs, mainly oleic acid, which in turn can enhance αS toxicity and aggregation. Thus, reduction of MUFAs synthesis by inhibition of stearoyl-CoA desaturase (SCD) activity could be the new way to prevent aggravation of αS pathology. Due to the limited distribution in peripheral tissues, SCD5 is a potential target in novel therapies and therefore could be an important starting point in search for disease-modifying neuroprotective therapy. Here we summarize facts about physiology and pathology of αS, explain recently discovered lipid-αS interactions, review SCD function and involved mechanisms, present available SCD inhibitors and discuss their pharmacological potential in disease management. Modulation of MUFA synthesis, decreasing αS and lipid toxicity is clearly essential, but unexplored avenue in pharmacotherapy in Parkinson's disease and synucleinopathies.
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