Therapeutic potential of Parkin and its regulation in Parkinson’s disease

IF 5.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2024-11-03 DOI:10.1016/j.bcp.2024.116600
Narukkottil Safreena , Indu C. Nair , Goutam Chandra
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Abstract

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain substantia nigra, resulting in motor and non-motor symptoms. While the exact etiology of PD remains elusive, a growing body of evidence suggests that dysfunction in the parkin protein plays a pivotal role in the pathogenesis of the disease. Parkin is an E3 ubiquitin ligase that ubiquitinates substrate proteins to control a number of crucial cellular processes including protein catabolism, immune response, and cellular apoptosis. While autosomal recessive mutations in the PARK2 gene, which codes for parkin, are linked to an inherited form of early-onset PD, heterozygous mutations in PARK2 have also been reported in the more commonly occurring sporadic PD cases. Impairment of parkin’s E3 ligase activity is believed to play a pathogenic role in both familial and sporadic forms of PD. This article provides an overview of the current understanding of the mechanistic basis of parkin’s E3 ligase activity, its major physiological role in controlling cellular functions, and how these are disrupted in familial and sporadic PD. The second half of the manuscript explores the currently available and potential therapeutic strategies targeting parkin structure and/or function in order to slow down or mitigate the progressive neurodegeneration in PD.

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帕金森病中 Parkin 及其调控的治疗潜力。
帕金森病(Parkinson's disease,PD)是一种令人衰弱的神经退行性疾病,其特征是中脑黑质多巴胺能神经元的逐渐丧失,从而导致运动和非运动症状。虽然帕金森病的确切病因仍难以确定,但越来越多的证据表明,帕金蛋白的功能障碍在该病的发病机制中起着关键作用。Parkin是一种E3泛素连接酶,可泛素化底物蛋白,以控制一系列关键的细胞过程,包括蛋白质分解、免疫反应和细胞凋亡。Parkin编码的PARK2基因的常染色体隐性突变与早发型帕金森氏症的遗传形式有关,而在更常见的散发性帕金森氏症病例中也有PARK2基因杂合突变的报道。本文概述了目前对 Parkin 的 E3 连接酶活性的机理基础、它在控制细胞功能方面的主要生理作用以及这些作用在家族性和散发性帕金森病中是如何被破坏的认识。手稿的后半部分探讨了针对帕金蛋白结构和/或功能的现有和潜在治疗策略,以减缓或减轻帕金森病的进行性神经变性。
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来源期刊
Biochemical pharmacology
Biochemical pharmacology 医学-药学
CiteScore
10.30
自引率
1.70%
发文量
420
审稿时长
17 days
期刊介绍: Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.
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