Parkin truncating variants result in a loss-of-function phenotype

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Parkinson disease (PD) is a prevalent neurodegenerative disorder with a significant genetic component.
• Mutations in the PARK2 gene, encoding the E3 ubiquitin ligase parkin, are a common cause of autosomal recessive juvenile-onset PD.
• The functional impact of many identified parkin variants remains incompletely understood.

Purpose of the Study:

• To functionally characterize two truncating parkin variants (N52Mfs*29 and L358Rfs*77) prevalent in Portuguese and Spanish populations.
• To elucidate the pathogenic mechanisms underlying these specific parkin variants in PD.

Main Methods:

• Functional assays to assess protein stability, aggregation propensity, and subcellular localization.
• Analysis of parkin's E3 ligase activity, including self-ubiquitination and substrate ubiquitination (p62).
• Assessment of parkin's response to mitochondrial depolarization.

Main Results:

• Both N52Mfs*29 and L358Rfs*77 variants undergo premature proteasomal degradation, despite moderate protein levels.
• These variants exhibit aggregation-prone behavior and mislocalization; L358Rfs*77 shows unique nuclear mislocalization.
• While N52Mfs*29 impairs self-ubiquitination, L358Rfs*77 retains it, but both variants fail to ubiquitinate p62 and do not relocalize to depolarized mitochondria.

Conclusions:

• Truncating parkin variants lead to a loss of essential parkin functions, including substrate ubiquitination and mitochondrial quality control.
• These functional deficits confirm the causative role of N52Mfs*29 and L358Rfs*77 variants in Parkinson disease pathogenesis.
• The study highlights the importance of functional characterization for understanding PD genetic heterogeneity.