Loss of C9orf72 perturbs the Ran-GTPase gradient and generates compositionally diverse cytoplasmic Importin β-1 granules in motor and cortical neurons in vivo
McGoldrick, P.; Lau, A.; You, Z.; Durcan, T. M.; Robertson, J.
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Repeat expansions in C9orf72 cause Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) eliciting toxic effects through generation of RNA foci, dipeptide repeat proteins and/or loss of C9orf72 protein. Defects in nucleocytoplasmic transport (NCT) have been implicated as a pathogenic mechanism underlying repeat expansion toxicity. Here, we show that loss of C9orf72 causes neuronal specific phenotypes, disrupting the Ran-GTPase gradient both in vitro and in vivo. We describe compositionally different types of cytoplasmic Importin {beta}-1 granules that exhibit neuronal subtype-specific properties in vivo. We show that the abundance of Importin {beta}-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to bud from the nuclear envelope and are co-immunoreactive for G3BP1 and K63-ubiquitin. These findings link loss of C9orf72 protein to gain-of-function mechanisms and defects in NCT.
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