C. elegans as a Nestor Guillermo Progeria Syndrome Model

Abstract

Variety of tissues, leading to growth retardation, severe skeletal defects and scoliosis. The syndrome is caused by a single amino acid substitution (A12T) in BAF1 (Barrier to Autointegration Factor 1). BAF1 is a highly conserved chromatin binding protein implicated in nuclear envelope (NE) breakdown, assembly and repair as well as chromatin compaction. Its NE localization is interdependent of lamins and LEM-domain proteins (LAP2, emerin, and MAN1) and contributes to chromatin organization although BAF1 is also present in the nucleoplasm. We have modified the baf-1 locus in Caenorhabditis elegans to mimic the human NGPS mutation (baf-1(G12T)) to elucidate why a mutation in an essential protein expressed throughout development triggers the appearance of symptoms ~2 years after birth. We report that NE levels of lamin/LMN-1 and emerin/EMR-1 are reduced in baf-1(G12T) mutants, whereas errors in chromosome segregation are increased. The baf-1(G12T) mutation reduces fertility and lifespan and accelerates age-dependent nuclear morphology deterioration. Moreover, we found that baf-1(G12T) mutants are hypersensitive to NE perturbations, particularly to modifications affecting lamin/LMN-1. Like other progerias, NGPS-derived fibroblasts feature malformed nuclei. Importantly, a set of genes whose depletion alleviates the nuclear associated defects was unveiled by CRISPR-mediated gene knockout in NGPS fibroblasts. When orthologs were silenced by RNAi in C. elegans, several reduced the embryonic lethality of sensitized baf-1(G12T) mutants. This represents a first and encouraging list of candidate genes to be further explored for the development of NGPS therapies.