Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS

Abstract

C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, uncovering karyopherins and effectors of Ran-mediated nucleocytoplasmic transport, providing insight into potential disease mechanisms and therapeutic targets.

Timing and significance of pathological features inC9orf72expansion-associated frontotemporal dementia

“…Whether these neurons represent an early C9orf72-related pathological transition stage or a consequence of surgery, local tissue hypoxia, or epilepsy remains unclear. If these neurons reflect C9orf72 disease, nuclear TDP-43 depletion could have resulted from diminished TDP-43 expression or restricted access to the nucleus due to nucleocytoplasmic transport impairment (Freibaum et al, 2015;Jovicic et al, 2015;Zhang et al, 2015). Further work is needed to determine whether loss of nuclear TDP-43 in the absence of a TDP-43 inclusion relates to particular C9orf72-specific inclusions, as suggested in a recent study (Cooper-Knock et al, 2015).…”

Nucleocytoplasmic transport inC9orf72-mediated ALS/FTD

“…Although it remains unclear whether such defects caused by DPRs precede TDP-43 pathology, it has been suggested that DPR accumulation may precede TDP-43 accumulation in some C9-FTD patient brain. 34 Together with the fact that genes in the nucleocytoplasmic transport pathway are genetic modifiers of DPR toxicity in yeast, 17 these findings collectively raise the intriguing possibility that DPRs may disrupt nucleocytoplasmic transport independent of the HRE RNA.…”

“…[15][16][17] Cytoplasmic mislocalization and aggregation of nuclear proteins in ALS/FTD Protein aggregation is a pathological hallmark of neurodegenerative diseases including ALS/FTD, Alzheimer's, Parkinson's, and Huntington's diseases. 18 Cytoplasmic mislocalization and aggregation of TDP-43 (TAR DNA-binding protein of 43 k D ) is observed in >95% of ALS cases and »45% of FTD.…”

“…Consistent with these findings, unbiased genetic screens in Drosophila and yeast independently identified components of the nuclear pore complex (NPC) as additional genetic modifiers of HRE-mediated neurodegeneration. 16,17 Macromolecules enter and exit the nucleus through the nuclear pore complex (NPC), a large protein complex consisting of »30 subunits called nucleoporins (Nups). 23 Molecules smaller than »40 kilo Daltons (k D ) can passively cross the NPC, whereas those larger than »40 k D need active transport powered by GTP hydrolysis of Ran GTPase (Ran, Fig.…”

“…DPRs have also been shown to affect nucleocytoplasmic transport via an unknown mechanism, 17 possibly due to an interaction between DPRs and the NPC. Although it remains unclear whether such defects caused by DPRs precede TDP-43 pathology, it has been suggested that DPR accumulation may precede TDP-43 accumulation in some C9-FTD patient brain.…”