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Brain. 2017 Jan;140(1):13-26. doi: 10.1093/brain/aww197. Epub 2016 Aug 6.

Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

Author information

1
1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
2
2 Faculty of Chemistry and Chemical Technology, Večna pot 113, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
3
1 Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia boris.rogelj@ijs.si.
4
3 Biomedical Research Institute BRIS, Puhova 10, SI-1000 Ljubljana, Slovenia.

Abstract

Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration.

KEYWORDS:

C9ORF72; FUS; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; nucleocytoplasmic transport

PMID:
27497493
DOI:
10.1093/brain/aww197
[Indexed for MEDLINE]

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