Posted - February 2014 in Research Highlights
May be critical for nerve cell function
This study establishes the association between various proteins whose levels are affected by HSP mutations and the functioning of Lipid Droplets. The results suggest that long-term maintenance of nerve cell axons may be dependent on proper functioning of these Lipid Droplets.
Hereditary axonopathies are frequently caused by mutations in proteins that reside in the endoplasmic reticulum (ER). Which of the many ER functions are pathologically relevant, however, remains to be determined. REEP1 is an ER protein mutated in hereditary spastic paraplegia (HSP) and hereditary motor neuropathy (HMN). We found that HSP-associated missense variants at the N-terminus of REEP1 abolish ER-targeting, while two more central variants are either rare benign SNPs or confer pathogenicity via a different mechanism. The mis-targeted variants accumulate at lipid droplets (LDs). N-terminal tagging, deletion of the N-terminus, and expression of a minor REEP1 isoform had the same effect. We also confirmed an increase in LD size upon co-overexpression of atlastins and REEP1. Neither wild-type REEP1, LD-targeted HSP variants, nor a non LD-targeted HMN variant reproduced this effect when expressed alone.
We conclude that the N-terminus of REEP1 is necessary for proper targeting to and/or retention in the ER. The protein’s potential to also associate with LDs corroborates a synergistic effect with atlastins on LD size. Interestingly, LD size is also altered upon knockdown of seipin, mutations of which also cause HSP and HMN. Regulation of LDs may thus be an ER function critical for long-term axonal maintenance.
SOURCE: Hum Mutat. 2014 Jan 29. doi: 10.1002/humu.22521. [Epub ahead of print] PMID: 24478229 [PubMed – as supplied by publisher]
Functional Mutation Analysis Provides Evidence for a Role of REEP1 in Lipid Droplet Biology.
Falk J1, Rohde M, Bekhite MM, Sophie Neugebauer, Hemmerich P, Kiehntopf M, Deufel T, Hübner CA, Beetz C.
1Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.