| Autor: |
Philip McGoldrick, Agnes Lau, Zhipeng You, Thomas M. Durcan, Janice Robertson |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 42, Iss 3, Pp 112134- (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2023.112134 |
| Popis: |
Summary: A hexanucleotide (GGGGCC)n repeat expansion in C9orf72 causes 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 disrupts the Ran-GTPase gradient and NCT in vitro and in vivo. NCT disruption in vivo is enhanced by the presence of compositionally different types of cytoplasmic Importin β-1 granule that exhibit neuronal subtype-specific properties. We show that the abundance of Importin β-1 granules is increased in the context of C9orf72 deficiency, disrupting interactions with nuclear pore complex proteins. These granules appear to associate with 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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