Abstract
Repeat expansions in the C9orf72 gene cause amyotrophic lateral sclerosis and frontotemporal dementia characterized by dipeptide-repeat protein (DPR) inclusions. The toxicity associated with two of these DPRs, poly-GR and poly-PR, has been associated with nucleocytoplasmic transport. To investigate the causal role of poly-GR or poly-PR on active nucleocytoplasmic transport, we measured nuclear import and export in poly-GR or poly-PR expressing Hela cells, neuronal-like SH-SY5Y cells and iPSC-derived motor neurons. Our data strongly indicate that poly-GR and poly-PR do not directly impede active nucleocytoplasmic transport.
Highlights
Repeat expansions in the C9orf[72] gene cause amyotrophic lateral sclerosis and frontotemporal dementia characterized by dipeptide-repeat protein (DPR) inclusions
DPRs are toxic in both cell culture and animal models, with the arginine containing poly-GR and poly-PR peptides as the most toxic ones, the exact pathological mechanisms by which these DPRs contribute to neurodegeneration in C9orf72-amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) patients remains disputed
Classical nuclear import is the most prevalent import pathway in the cell[19] and its disturbance has been suggested to underlie cytoplasmic mislocalization of TAR DNAbinding protein 43 (TDP-43)[20], which is a prominent hallmark of ALS and FTD21
Summary
Repeat expansions in the C9orf[72] gene cause amyotrophic lateral sclerosis and frontotemporal dementia characterized by dipeptide-repeat protein (DPR) inclusions. To investigate the causal role of poly-GR or poly-PR on active nucleocytoplasmic transport, we measured nuclear import and export in poly-GR or poly-PR expressing Hela cells, neuronal-like SH-SY5Y cells and iPSC-derived motor neurons. A reduced import has been measured in C9orf72-iPSC-derived motor neurons[11,16] These data argue for an important role of nucleocytoplasmic transport in the pathogenic mechanisms underlying C9orf72-ALS/FTD. FG Nups have a low sequence complexity[17] and undergo phase separation into a dense polymer meshwork which constitute the nucleopore complex (NPC) permeability barrier[18] This raises the intriguing possibility that poly-GR and poly-PR causally affect motor neuron health through disturbing nucleocytoplasmic transport directly.
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