Prefoldin 5 Is Required for Normal Sensory and Neuronal Development in a Murine Model

Yongsuk Lee,Richard S Smith,Wanda Jordan,Benjamin L King,Jungyeon Won,Jose M Valpuesta,Jurgen K Naggert,Patsy M Nishina

doi:10.1074/jbc.m110.177352

Abstract

Molecular chaperones and co-chaperones are crucial for cellular development and maintenance as they assist in protein folding and stabilization of unfolded or misfolded proteins. Prefoldin (PFDN), a ubiquitously expressed heterohexameric co-chaperone, is necessary for proper folding of nascent proteins, in particular, tubulin and actin. Here we show that a genetic disruption in the murine Pfdn5 gene, a subunit of prefoldin, causes a syndrome characterized by photoreceptor degeneration, central nervous system abnormalities, and male infertility. Our data indicate that a missense mutation in Pfdn5, may cause these phenotypes through a reduction in formation of microtubules and microfilaments, which are necessary for the development of cilia and cytoskeletal structures, respectively. The diversity of phenotypes demonstrated by models carrying mutations in different PFDN subunits suggests that each PFDN subunit must confer a distinct substrate specificity to the prefoldin holocomplex.

Highlights

Health Grants EY016501 and EY11996. 1 To whom correspondence should be addressed: The Jackson Laboratory, from the chaperonin containing TCP1 (CCT) [4]
A Point Mutation in the Prefoldin 5 (Pfdn5) Gene Leads to the nmf5a Mouse Phenotypes—The Neuroscience Mutagenesis Facility (NMF) at The Jackson Laboratory identified an ENU (N-ethyl-N-nitrosourea)-derived mouse model, nmf5, which was severely runted, presented with a retinal degenerative phenotype, and died shortly after weaning age
The leucine residue is highly conserved across species, and in the 7 divergent mouse strains in which prefoldin subunit-5 (Pfdn5) was sequenced, none showed a guanosine at nucleotide 329

Summary

Introduction

Health Grants EY016501 and EY11996. 1 To whom correspondence should be addressed: The Jackson Laboratory, from the CCT [4]. Sakono et al [16] suggested that improper function of prefoldin may be involved in the formation of toxic soluble ␤-amyloid oligomers, a common pathology observed in neurodegenerative diseases. In support of this notion, a number of human neurodegenerative diseases associated with genetic mutations in actin, tubulin, tubulin-associated proteins, and chaperones have been described [15, 17,18,19,20,21]. Reduced availability of microfilament and microtubules, necessary for development of cellular structures, is likely to contribute to the cytoskeletal and ciliary abnormalities that underlie the disease pathologies observed in Pfdn5nmf5a mutants

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Conclusion