Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.
Acta Neuropathol
; 144(3): 413-435, 2022 09.
Article
en En
| MEDLINE
| ID: mdl-35778567
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Unión al ADN
/
Células Madre Pluripotentes Inducidas
/
Antígeno Ventral Neuro-Oncológico
/
Esclerosis Amiotrófica Lateral
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Acta Neuropathol
Año:
2022
Tipo del documento:
Article
País de afiliación:
Alemania