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

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.

Prefoldin Protects Neuronal Cells from Polyglutamine Toxicity by Preventing Aggregation Formation

“…Intriguingly, PFD1 knock-out mice show neuronal loss in the cerebellum and defects in lymphocyte development (47). PFD5-L110R mutant mice also showed that PFD5 missense mutation causes neurodegeneration, photoreceptor degeneration, and male infertility (48). These observations suggest that prefoldin plays a pivotal role in maintenance of neuronal cell activity.…”

“…a.u., arbitrary unit. tion, including transcriptional regulation for PFD5 (49,50) and PFD4 (51) and DNA binding activity for PFD1 and PFD2 (52), and that there are some distinctive phenotypes between PFD1-null and PFD5-L110R mice (47,48). PFD5/MM-1 is known to act as a c-MYC-binding protein that suppresses cell growth and transformation independently of the prefoldin complex (49,53).…”

The role of primary cilia in the development and disease of the retina

“…[44][45][46] Growth of the microtubule axoneme is dependent on chaperone proteins such as prefoldin-5 that, when mutated in mice, leads to photoreceptor degeneration. 47 Other chaperones including HSC70 (Hspa8) have also been found to be associated with photoreceptor axonemal proteins. 48 Glutamylation of axonemal tubulin is essential for normal photoreceptor development and function, 49 and the stabilization of axonemal microtubules by other post-translational modifications such as acetylation are also presumably required for these normal processes.…”

Prefoldin Plays a Role as a Clearance Factor in Preventing Proteasome Inhibitor-induced Protein Aggregation

“…PFD2 makes a large protein complex to regulate the expression of nutrition-related genes (17). Mice harboring a missense mutation of the MM-1␣/PFD5 gene that causes an amino acid substitution from leucine to arginine at amino acid number 110 (L100R) have recently been established after exposure of mice to N-ethyl-N-nitrosourea (18). L100R MM-1␣ mice exhibit various phenotypes, including cerebellar atrophy with death of Purkinje cells and male infertility (18).…”