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A mutational atlas for Parkin proteostasis.

Lene Clausen¹, Vasileios Voutsinos¹, Matteo Cagiada¹

¹Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark.

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|February 20, 2024

Summary

Parkin gene variants causing Parkinsonism are often proteasome targets due to destabilized protein structures. This study maps Parkin variants, revealing degradation signals that explain disease mechanisms.

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Area of Science:

Biochemistry
Genetics
Neuroscience

Background:

Protein homeostasis (proteostasis) is crucial for cellular function.
Mutations affecting protein folding and stability can lead to diseases like Parkinsonism.
The ubiquitin ligase Parkin is implicated in autosomal recessive Parkinsonism due to gene variants.

Purpose of the Study:

To investigate the pathological mechanisms of Parkin variants.
To provide comprehensive genotype-phenotype information for Parkin variants.
To map Parkin variant abundance and identify degradation signals.

Main Methods:

Variant abundance by massively parallel sequencing (VAMP-seq) was used.
Quantified Parkin variant abundance in cultured human cells.
Generated a mutational map of single-site amino acid substitutions and nonsense variants.

Main Results:

Most low-abundance Parkin variants are proteasome targets within structured domains.
Half of known disease-linked Parkin variants exhibit low abundance.
Identified an exposed degron region near the Parkin activation element.

Conclusions:

Missense variants can cause protein degradation by destabilizing the native protein.
Alternatively, missense variants can introduce local degradation signals.
This work elucidates how Parkin variants contribute to Parkinsonism through protein degradation pathways.