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Role of Deubiquitinases in Parkinson's Disease-Therapeutic Perspectives.

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder that has been associated with mitochondrial dysfunction, oxidative stress, and defects in mitophagy as well as α-synuclein-positive inclusions, termed Lewy bodies (LBs), which are a common pathological hallmark in PD. Mitophagy is a process that maintains cellular health by eliminating dysfunctional mitochondria, and it is triggered by ubiquitination of mitochondrial-associated proteins-e.g., through the PINK1/Parkin pathway-which results in engulfment by the autophagosome and degradation in lysosomes. Deubiquitinating enzymes (DUBs) can regulate this process at several levels by deubiquitinating mitochondrial substrates and other targets in the mitophagic pathway, such as Parkin. Moreover, DUBs can affect α-synuclein aggregation through regulation of degradative pathways, deubiquitination of α-synuclein itself, and/or via co-localization with α-synuclein in inclusions. DUBs with a known association to PD are described in this paper, along with their function. Of interest, DUBs could be useful as novel therapeutic targets against PD through regulation of PD-associated defects.

SUBMITTER: Nielsen PYO

PROVIDER: S-EPMC9954239 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Role of Deubiquitinases in Parkinson's Disease-Therapeutic Perspectives.

Nielsen Pernille Y Ø PYØ Okarmus Justyna J Meyer Morten M

Cells 20230217 4

Parkinson's disease (PD) is a neurodegenerative disorder that has been associated with mitochondrial dysfunction, oxidative stress, and defects in mitophagy as well as α-synuclein-positive inclusions, termed Lewy bodies (LBs), which are a common pathological hallmark in PD. Mitophagy is a process that maintains cellular health by eliminating dysfunctional mitochondria, and it is triggered by ubiquitination of mitochondrial-associated proteins-e.g., through the PINK1/Parkin pathway-which results ...[more]

PMID: 36831318

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Project description:The molecular platforms of the innate immune system are essential to recognize pathologic external factors that are crucial to differentiate these danger signals from host motifs. A set of sensors recognizing pathologic factors is present and defined as a membrane-bound family of Toll-like receptors as well as the cytosolic ones including the family of nucleotide-binding domain leucine-rich repeat proteins. In this regard, the inflammasomes have been identified as an innate immune sensor toward pathologic external factors as well as endogenous damage-associated molecular pattern signals transducing from the above-mentioned receptors to gene expressions. Recent research has shown novel findings in inflammasome biology and genetics which lead to the alteration of diagnosis and management in autoinflammatory diseases as well as developing novel treatments, including the examples of nucleotide-binding domain leucine-rich repeat proteins-inflammasomes and pyrin-inflammasomes. The pyrin protein is encoded by the Mediterranean Fever gene on chromosome 16 that acts as a major regulatory component of the inflammasome, and is responsible for familial Mediterranean fever. We have recently examined the whole nucleotide sequence of the Mediterranean Fever gene in Japanese familial Mediterranean fever patients and revealed single nucleotide variants associated with the susceptibility of familial Mediterranean fever from a nation-wide survey by the next-generation sequencing. In a cytokine profile analysis of familial Mediterranean fever patients, we have found that interleukin-6 is considered to be one of the most crucial cytokines in familial Mediterranean fever attack since interleukin-6 had the best performance for distinguishing familial Mediterranean fever in attack from healthy controls or familial Mediterranean fever in remission, and in vitro interleukin-6 production is regulated by microRNAs-204-3p/phosphoinositide 3-kinase g pathway. Accordingly, we have been investigating the efficacy and safety of anti-human interleukin-6 receptor monoclonal antibody, tocilizumab, in patients with familial Mediterranean fever refractory or intolerant to colchicine through an investigator-initiated clinical trial supported by the Japan Agency for Medical Research and Development. Like interleukin-1b, interleukin-18 can be processed by caspase-1 and proteinase-3 to be activated within the inflammasomes. We have also found the importance of interleukin-18 in several autoinflammatory conditions. Recently, the concept of autoinflammation is widely distributed into many common diseases; thus, the attention to a wide spectrum of diseases MEFV gene deeply involved is required.

Dataset Information

Role of Deubiquitinases in Parkinson's Disease-Therapeutic Perspectives.

Publications

Role of Deubiquitinases in Parkinson's Disease-Therapeutic Perspectives.

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