Liquid-liquid phase separation and conformational strains of α-Synuclein: implications for Parkinson's disease pathogenesis.

IF 3.5 3区 医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI:10.3389/fnmol.2024.1494218
Eva D Ruiz-Ortega, Anna Wilkaniec, Agata Adamczyk
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Abstract

Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (α-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of α-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in β-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of α-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in α-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid-liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin α-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in α-syn conformational rearrangement, which may lead to pathology and the existence of different α-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in α-syn pathology.

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α-突触核蛋白的液-液相分离和构象应变:对帕金森病发病机制的影响
帕金森病(PD)和其他突触核蛋白病的特征是α-突触核蛋白(α-syn)在脑细胞中聚集和沉积,形成路易体(LB)和路易神经元(LN)等不溶性内含物。α-syn的聚集是一个复杂的过程,涉及从其原生无规线圈到富含β片的明确二级结构的结构转换,形成淀粉样纤维。有证据表明,在这一转换过程中形成的 α-syn 聚集体的中间物质是导致细胞死亡的原因。然而,参与α-syn聚集的分子事件及其与疾病发病和进展的关系仍未完全阐明。此外,在各种突触核蛋白病中观察到的临床和病理异质性也很突出。液-液相分离(LLPS)和凝结物形成被认为是支撑α-syn病理的替代机制,也是造成突触核蛋白病异质性的原因之一。本综述侧重于细胞环境在α-syn构象重排中的作用,这可能会导致病理变化,以及存在具有不同毒性模式的不同α-syn构象株。讨论将包括细胞压力、异常 LLPS 的形成以及 LLPS 在 α-syn 病理学中的潜在作用。
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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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