YOD1 attenuates neurogenic proteotoxicity through its deubiquitinating activity

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Ubiquitination is a key post-translational modification.
• Deubiquitinases (DUBs) reverse ubiquitination.
• YOD1 is a DUB implicated in ER stress, but its role in neurodegeneration is unknown.

Purpose of the Study:

• To investigate the role of YOD1 in neurodegenerative diseases.
• To determine YOD1's deubiquitinating activity and substrate specificity.
• To examine YOD1's involvement in the degradation of disease-associated mutant proteins.

Main Methods:

• Assessed YOD1's deubiquitinating activity and linkage preference (K48/K63).
• Measured YOD1 expression under various stress conditions, including those induced by neurodegenerative disease proteins.
• Investigated YOD1 localization in Parkinson's disease patient samples.

Main Results:

• YOD1 exhibits deubiquitinating activity towards K48- and K63-linked ubiquitin.
• YOD1 expression is upregulated by stress and neurotoxic proteins linked to Huntington's and Parkinson's diseases.
• YOD1 reduces cytotoxicity by degrading mutant proteins, a process dependent on its catalytic activity.
• YOD1 localizes to Lewy bodies in Parkinson's disease.

Conclusions:

• YOD1 is a catalytically active deubiquitinase involved in cellular stress responses.
• YOD1 plays a significant role in the pathogenesis of neurodegenerative diseases.
• YOD1 may represent a therapeutic target for neurodegenerative disorders by modulating protein degradation pathways.