DNAJC13 p.Asn855Ser, implicated in familial parkinsonism, alters membrane dynamics of Sorting Nexin 1.

DNAJC13 p.Asn855Ser, implicated in familial parkinsonism, alters membrane dynamics of Sorting Nexin 1.

Publication date: May 10, 2019

DNAJC13 (RME-8) is a core co-chaperone that facilitates membrane recycling and cargo sorting of endocytosed proteins. DNAJ/Hsp40 (heat shock protein 40) proteins are highly conserved throughout evolution and mediate the folding of nascent proteins, and the unfolding, refolding or degradation of misfolded proteins, while assisting in associated-membrane translocation. DNAJC13 is one of five DNAJ ‘C’ class chaperone variants implicated in monogenic parkinsonism. Here we examine the effect of the DNAJC13 disease-linked mutation (p.Asn855Ser) on its interacting partners, focusing on sorting nexin 1 (SNX1) membrane dynamics in primary cortical neurons derived from a novel Dnajc13 p.Asn855Ser knock-in (DKI) mouse model. Dnajc13 p.Asn855Ser mutant and wild type protein expression were equivalent in mature heterozygous cultures (DIV21). While SNX1-positive puncta density, area, and WASH-retromer assembly were comparable between cultures derived from DKI and wild type littermates, the formation of SNX1-enriched tubules in DKI neuronal cultures was significantly increased. Thus, Dnajc13 p.Asn855Ser disrupts SNX1 membrane-tubulation and trafficking, analogous to results from RME-8 depletion studies. The data suggest the mutation confers a dominant-negative gain-of-function in RME-8. Implications for the pathogenesis of Parkinson’s disease are discussed.

Follett, J., Fox, J.D., Gustavsson, E.K., Kadgien, C., Munsie, L.N., Cao, L.P., , Tatarnikov, Milnerwood, A.J., and Farrer, M.J. DNAJC13 p.Asn855Ser, implicated in familial parkinsonism, alters membrane dynamics of Sorting Nexin 1. 20757. 2019 Neurosci Lett.

Concepts Keywords
Assembly DNAJC13
Chaperone Chaperone DnaJ
Cortical Sorting nexin
Endocytosed SNX1
Evolution Heat shock proteins
Heat Shock Retromer
Heterozygous Cell biology
Membrane Biochemistry
Misfolded Proteins Protein domains
Monogenic Branches of biology
Mutant
Mutation
Neurons
Parkinson
Parkinsonism
Pathogenesis
Recycling
Translocation
WASH

Semantics

Type Source Name
gene UNIPROT WASHC1
gene UNIPROT SNX1
disease MESH shock
gene UNIPROT DNAJB1
gene UNIPROT DNAJC14
gene UNIPROT DNAJA2
gene UNIPROT DNAJB6
disease MESH familial
gene UNIPROT DNAJC13

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *