Deubiquitinating enzymes in parkinson’s disease: molecular mechanisms and therapeutic potential

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of α-synuclein aggregates and the selective degeneration of dopaminergic neurons in the substantia nigra. Growing evidence implicates dysfunction of the ubiquitin-proteasome system (UPS), a critical regulator of protein homeostasis, in the pathogenesis of PD through impaired clearance of toxic protein species. As key components of the UPS, deubiquitinating enzymes (DUBs) counterbalance ubiquitin ligase activity by cleaving ubiquitin chains from substrate proteins, thereby playing pivotal roles in maintaining protein turnover and regulating cellular signaling pathways. Notably, emerging research has demonstrated that specific DUBs are intimately involved in modulating multiple PD-related pathological processes, including α-synuclein aggregation, mitochondrial oxidative stress, iron homeostasis, and neuronal survival. These findings suggest DUBs as promising therapeutic targets for PD intervention. This review comprehensively summarize the pathophysiological roles of PD-associated DUBs, their molecular mechanisms in disease progression, and recent advances in the development of DUB inhibitors as potential disease-modifying therapies for PD. DUB dysfunction is mechanistically linked to PD pathogenesis. DUBs integrate proteostasis imbalance and neurodegeneration by regulating α-synuclein dynamics, mitochondrial integrity, and neuronal survival. Specific DUB modulators significantly ameliorate PD-related pathologies. DUB-targeted strategies offer superior multi-pathway intervention compared to conventional single-target therapies for PD.

• Publication year

  2025

• Venue

  Molecular Medicine

• Publication date

  2025-11-07

• Fields of study

  Medicine

• Identifiers
  DOI 10.1186/s10020-025-01389-xPMID 41204197PMCID 12593799
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Therapeutic targeting of ubiquitin-specific protease 7 (USP7): Mechanistic insights, dysregulation, and advances in drug discovery.

  2025cited by this paper
• Mechanistic Insights into the Mechanism of Allosteric Inhibition of Ubiquitin-Specific Protease 7 (USP7)

  2025cited by this paper
• Deubiquitinating enzymes at the crossroads of blood–brain barrier integrity and neurodegeneration: mechanistic insights, therapeutic targeting and future directions

  2025cited by this paper
• The deubiquitinase OTUD3 stabilizes IRP2 expression to reduce hippocampal neuron ferroptosis via the p53/PTGS2 pathway to ameliorate cerebral ischemia–reperfusion injury

  2024cited by this paper
• α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease

  2024cited by this paper
• Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization

  2024cited by this paper
• Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson’s disease

  2024cited by this paper
• E3 ligases and DUBs target ferroptosis: A potential therapeutic strategy for neurodegenerative diseases.

  2024cited by this paper
• USP26 promotes colorectal cancer tumorigenesis by restraining PRKN-mediated mitophagy

  2024cited by this paper
• Ubiquitin Carboxyl-Terminal Hydrolase L1 and Its Role in Parkinson’s Disease

  2024cited by this paper
• The pathogenesis of Parkinson's disease.

  2024cited by this paper
• Deubiquitinating enzyme YOD1 deubiquitinates and destabilizes α-synuclein.

  2023cited by this paper
• Role of Deubiquitinases in Parkinson’s Disease—Therapeutic Perspectives

  2023cited by this paper
• Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones

  2023cited by this paper
• Trans-Regulation of Alternative PD-L1 mRNA Processing by CDK12 in Non-Small-Cell Lung Cancer Cells

  2023cited by this paper
• USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice

  2023cited by this paper
• The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency.

  2023cited by this paper
• Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model

  2023cited by this paper
• The Role of Ubiquitin–Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease

  2023cited by this paper
• Proteolysis-Targeting Chimera (PROTAC) Delivery into the Brain across the Blood-Brain Barrier

  2023cited by this paper
• Circulating Tumor DNA in the Management of Early-Stage Breast Cancer

  2023cited by this paper
• Dopamine D1 Agonists: First Potential Treatment for Late-Stage Parkinson’s Disease

  2023cited by this paper
• USP8 Down-Regulation Promotes Parkin-Independent Mitophagy in the Drosophila Brain and in Human Neurons

  2023cited by this paper
• Site-Specific Detection and Characterization of Ubiquitin Carbamylation.

  2022cited by this paper
• High-Phosphate-Stimulated Macrophage-Derived Exosomes Promote Vascular Calcification via let-7b-5p/TGFBR1 Axis in Chronic Kidney Disease

  2022cited by this paper
• Role of the OTUB1/IRF7/NOX4 axis in oxidative stress injury and inflammatory responses in mice with Parkinson's disease

  2022cited by this paper
• The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases

  2022cited by this paper
• Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

  2022cited by this paper
• The disturbance of protein synthesis/degradation homeostasis is a common trait of age-related neurodegenerative disorders.

  2022cited by this paper
• CRISPR/Cas9-based genome-wide screening for deubiquitinase subfamily identifies USP1 regulating MAST1-driven cisplatin-resistance in cancer cells

  2022cited by this paper
• Cerebral Iron Deposition in Neurodegeneration

  2022cited by this paper
• S-Nitrosylation of OTUB1 Alters Its Stability and Ubc13 Binding.

  2022cited by this paper
• Deubiquitylase OTUD3 prevents Parkinson’s disease through stabilizing iron regulatory protein 2

  2022cited by this paper
• Novel Imidazole Phenoxyacetic Acids as Inhibitors of USP30 for Neuroprotection Implication via the Ubiquitin-Rho-110 Fluorometric Assay: Design, Synthesis, and In Silico and Biochemical Assays.

  2022cited by this paper
• Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress

  2022cited by this paper
• Cellular functions regulated by deubiquitinating enzymes in neurodegenerative diseases.

  2021cited by this paper
• The Ubiquitin–Proteasome System in Immune Cells

  2021cited by this paper
• Small-Molecule Inhibitors Targeting Proteasome-Associated Deubiquitinases

  2021cited by this paper
• Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases

  2021cited by this paper
• Precise control of mitophagy through ubiquitin proteasome system and deubiquitin proteases and their dysfunction in Parkinson’s disease

  2021cited by this paper
• Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus

  2021cited by this paper
• USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation

  2020cited by this paper
• Proteasome Subunits Involved in Neurodegenerative Diseases.

  2020cited by this paper
• Small-molecule inhibitors of α-synuclein for the treatment of Parkinson's disease: a patent landscape.

  2020cited by this paper
• Deubiquitinating Enzymes in Parkinson’s Disease

  2020cited by this paper
• Amyloid aggregates of the deubiquitinase OTUB1 are neurotoxic, suggesting that they contribute to the development of Parkinson's disease

  2020cited by this paper
• The deubiquitinase JOSD2 is a positive regulator of glucose metabolism

  2020cited by this paper
• USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy

  2020cited by this paper
• Ubiquitin receptors are required for substrate-mediated activation of the proteasome’s unfolding ability

  2019cited by this paper
• Impressionist portraits of mitotic exit: APC/C, K11-linked ubiquitin chains and Cezanne

  2019cited by this paper
• α-Synuclein misfolding and aggregation: Implications in Parkinson's disease pathogenesis.

  2019cited by this paper
• Breaking the chains: deubiquitylating enzyme specificity begets function

  2019cited by this paper
• YOD1 attenuates neurogenic proteotoxicity through its deubiquitinating activity.

  2018cited by this paper
• In a Class of Its Own: A New Family of Deubiquitinases Promotes Genome Stability.

  2018cited by this paper
• USP14 inhibition corrects an in vivo model of impaired mitophagy

  2018cited by this paper
• Dual Function of USP14 Deubiquitinase in Cellular Proteasomal Activity and Autophagic Flux.

  2018cited by this paper
• Deubiquitylating enzymes and drug discovery: emerging opportunities

  2017cited by this paper
• An inhibitor of the proteasomal deubiquitinating enzyme USP14 induces tau elimination in cultured neurons

  2017cited by this paper
• Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

  2016cited by this paper
• Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease

  2016cited by this paper
• Ubiquitin chain diversity at a glance

  2016cited by this paper
• Familial Mutations and Post-translational Modifications of UCH-L1 in Parkinson’s Disease and Neurodegenerative Disorders

  2015cited by this paper
• Assembly and Specific Recognition of K29- and K33-Linked Polyubiquitin

  2015cited by this paper
• Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies.

  2015cited by this paper
• USP8 and PARK2/parkin-mediated mitophagy

  2015cited by this paper
• The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy

  2014cited by this paper
• Small-Molecule RA-9 Inhibits Proteasome-Associated DUBs and Ovarian Cancer In Vitro and In Vivo via Exacerbating Unfolded Protein Responses

  2014cited by this paper
• The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy

  2014cited by this paper
• A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

  2014cited by this paper
• The parallel reaction monitoring method contributes to a highly sensitive polyubiquitin chain quantification.

  2013cited by this paper
• Chalcone-based small-molecule inhibitors attenuate malignant phenotype via targeting deubiquitinating enzymes

  2012cited by this paper
• α-Synuclein fate is determined by USP9X-regulated monoubiquitination

  2011cited by this paper
• K11-linked polyubiquitination in cell cycle control revealed by a K11 linkage-specific antibody.

  2010cited by this paper
• Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis.

  2010cited by this paper
• Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant.

  2007cited by this paper
• UCH‐L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease

  2004cited by this paper
• BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair.

  2004cited by this paper
• Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants.

  2003cited by this paper
• The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.

  2002cited by this paper
• The UCH-L1 gene encodes two opposing enzymatic activities that affect-synuclein degradation and Park

  2002cited by this paper
• Pathogenesis of Parkinson's disease.

  1992cited by this paper

• No citing papers are available for this paper.