Unknown

Dataset Information

0

Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization.


ABSTRACT: Nucleolar stress has been implicated in the pathology and disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) from repeat expansions of GGGGCC in C9orf72 (C9-ALS/FTLD) but not in sporadic ALS (SALS). Previously we reported that antisense RNA transcripts are unique in C9-ALS because of their nucleolar localization in spinal motor neurons and correlation with TDP-43 mislocalization, the hallmark proteinopathy of ALS and FTLD. Here we report our further studies of 11 SALS, 11 C9-ALS and 11 control spinal cords. We find that nucleolar stress manifests specifically as shrinkage in nucleoli of C9-ALS spinal motor neurons. Nucleolar size reduction is greatest in similarly sized alpha motor neurons from C9-ALS cases and results are not skewed by the number of surviving neurons from each ALS spinal cord. Surprisingly, nucleolar shrinkage occurs before main pathological hallmarks-TDP-43 mislocalization or antisense RNA foci-appear and this suggest that nucleolar stress can precede pathology in C9-ALS, findings previously identified in C9-FTLD using sense RNA foci and dipeptide repeat proteins as pathological markers. Importantly, these observations are also seen in SALS motor neurons and thus nucleolar stress appears to be a significant and probably upstream problem in sporadic disease.

SUBMITTER: Aladesuyi Arogundade O 

PROVIDER: S-EPMC7885352 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization.

Aladesuyi Arogundade Olubankole O   Nguyen Sandra S   Leung Ringo R   Wainio Danielle D   Rodriguez Maria M   Ravits John J  

Acta neuropathologica communications 20210215 1


Nucleolar stress has been implicated in the pathology and disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) from repeat expansions of GGGGCC in C9orf72 (C9-ALS/FTLD) but not in sporadic ALS (SALS). Previously we reported that antisense RNA transcripts are unique in C9-ALS because of their nucleolar localization in spinal motor neurons and correlation with TDP-43 mislocalization, the hallmark proteinopathy of ALS and FTLD. Here we report our  ...[more]

Similar Datasets

| S-EPMC4468790 | biostudies-literature
| S-EPMC7035286 | biostudies-literature
| S-EPMC4596857 | biostudies-literature
| S-EPMC5409121 | biostudies-literature
| S-EPMC4937342 | biostudies-literature
| S-EPMC7888715 | biostudies-literature
| S-EPMC8622279 | biostudies-literature
| S-EPMC5660202 | biostudies-literature
| EMPIAR-10831 | biostudies-other