Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain.

Area of Science:

• Molecular Biology
• Neurodegenerative Diseases
• Protein Folding

Background:

• Protein misfolding and aggregation are hallmarks of degenerative diseases.
• Heat shock proteins (HSPs), like DNAJB6, are crucial for protein homeostasis.
• Mutations in DNAJB6 have been linked to Limb-Girdle Muscular Dystrophy type 1D (LGMDD1).

Purpose of the Study:

• To characterize novel J domain mutations in DNAJB6 associated with LGMDD1.
• To investigate the functional impact of these mutations on chaperone activity.
• To understand the role of DNAJB6 in skeletal muscle and identify its client proteins.

Main Methods:

• Utilized the yeast system, employing homologous protein Sis1 to DNAJB6.
• Conducted phenotypic, biochemical, and functional assays.
• Assessed the effect of homologous J domain mutations on Sis1 function.

Main Results:

• Homologous mutations in the Sis1 J domain differentially affected prion strain propagation.
• These mutations also altered the processing of a non-prion substrate.
• Demonstrated aberrant chaperone function due to J domain mutations.

Conclusions:

• Newly identified J domain mutations in DNAJB6 lead to aberrant chaperone function.
• This dysfunction is implicated in the pathogenesis of LGMDD1.
• The study provides insights into DNAJB6's role in protein quality control and disease.