Nuclear-Import Receptors Counter Deleterious Phase Transitions in Neurodegenerative Disease.
J Mol Biol
; 434(1): 167220, 2022 01 15.
Article
em En
| MEDLINE
| ID: mdl-34464655
ABSTRACT
Nuclear-import receptors (NIRs) engage nuclear-localization signals (NLSs) of polypeptides in the cytoplasm and transport these cargo across the size-selective barrier of the nuclear-pore complex into the nucleoplasm. Beyond this canonical role in nuclear transport, NIRs operate in the cytoplasm to chaperone and disaggregate NLS-bearing clients. Indeed, NIRs can inhibit and reverse functional and deleterious phase transitions of their cargo, including several prominent neurodegenerative disease-linked RNA-binding proteins (RBPs) with prion-like domains (PrLDs), such as TDP-43, FUS, EWSR1, TAF15, hnRNPA1, and hnRNPA2. Importantly, elevated NIR expression can mitigate degenerative phenotypes connected to aberrant cytoplasmic aggregation of RBPs with PrLDs. Here, we review recent discoveries that NIRs can also antagonize aberrant interactions and toxicity of arginine-rich, dipeptide-repeat proteins that are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) caused by G4C2 hexanucleotide repeat expansions in the first intron of C9ORF72. We also highlight recent findings that multiple NIR family members can prevent and reverse liquid-liquid phase separation of specific clients bearing RGG motifs in an NLS-independent manner. Finally, we discuss strategies to enhance NIR activity or expression, which could have therapeutic utility for several neurodegenerative disorders, including ALS, FTD, multisystem proteinopathy, limbic-predominant age-related TDP-43 encephalopathy, tauopathies, and related diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Citoplasmáticos e Nucleares
/
Doenças Neurodegenerativas
Limite:
Humans
Idioma:
En
Revista:
J Mol Biol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos