Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.

IF 3.3 3区 医学 Q2 NEUROSCIENCES
Casey J Lumpkin, Hiral Patel, Gregory K Potts, Shilpi Chaurasia, Lauren Gibilisco, Gyan P Srivastava, Janice Y Lee, Nathan J Brown, Patricia Amarante, Jon D Williams, Eric Karran, Matthew Townsend, Dori Woods, Brinda Ravikumar
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引用次数: 0

Abstract

Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.

对M83神经元中种子诱导的α-突触核蛋白聚集进行的广义蛋白质组学分析揭示了可能导致帕金森病发病机制的蛋白质稳态机制重塑。
折叠错误的α-突触核蛋白(α-syn)的聚集是帕金森病(PD)和相关突触核蛋白病的一个主要特征。这些聚集体的性质及其对细胞功能障碍的作用仍未得到清楚的阐明。我们采用基于质谱的总蛋白组学和磷酸化蛋白组学方法,利用帕金森病的 M83 小鼠原发性神经元模型来描述 α-syn 聚集引起的潜在分子和生物学变化。我们确定了蛋白质组中的重大变化,这些变化与这些神经元中形成的大型路易体样 α-syn 聚集相吻合。我们利用基于蛋白质-蛋白质相互作用(PPI)的网络分析,确定了调节可能失调的特定生物通路的关键蛋白质群,并确定了调节蛋白质稳态(proteostasis)的几种机制。蛋白质组中观察到的变化可能包括α-syn聚集引起的平衡补偿和失调,进一步了解这两个过程及其在α-syn相关蛋白稳态中的作用,可能有助于改进对帕金森病及相关疾病患者的治疗方案。
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来源期刊
Molecular Brain
Molecular Brain NEUROSCIENCES-
CiteScore
7.30
自引率
0.00%
发文量
97
审稿时长
>12 weeks
期刊介绍: Molecular Brain is an open access, peer-reviewed journal that considers manuscripts on all aspects of studies on the nervous system at the molecular, cellular, and systems level providing a forum for scientists to communicate their findings. Molecular brain research is a rapidly expanding research field in which integrative approaches at the genetic, molecular, cellular and synaptic levels yield key information about the physiological and pathological brain. These studies involve the use of a wide range of modern techniques in molecular biology, genomics, proteomics, imaging and electrophysiology.
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