Mutations in the C9ORF72 gene are the most common genetic cause ALS and frontotemporal dementia. The gene itself codes for two protein isoforms, a long form (C9-L) and a short form (C9-S), whose functions remain elusive. Janice Robertson and her team at the University of Toronto in Ontario, Canada created antibodies to detect and distinguish the two isoforms, enabling them to examine their differential characteristics. In the July 14 Annals of Neurology online, the researchers report that the C9-S is localized to the nuclear membrane in healthy motor neurons, but to the plasma members in ALS motor neurons. Furthermore, the C9 isoforms interact with the nuclear pore complex, which shuttles proteins, including TDP-43, across the nuclear membrane. This study provides a link between mislocalization of TDP-43 from the nucleus to the cytoplasm, a pathological hallmark of ALS, and ALS-causing mutations in C9ORF72.
Full Amber Dance’s full report on the ALS Research Forum, click here.
Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, Keith J, Zinman L, Rogaeva E, Robertson J. Isoform Specific Antibodies Reveal Distinct Subcellular Localizations of C9orf72 in Amyotrophic Lateral Sclerosis. Ann Neurol. 2015 Jul 14. [Pubmed].