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

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 trans...

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Bibliographic Details
Published in:	Acta neuropathologica communications Vol. 9; no. 1; p. 26
Main Authors:	Aladesuyi Arogundade, Olubankole, Nguyen, Sandra, Leung, Ringo, Wainio, Danielle, Rodriguez, Maria, Ravits, John
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 15-02-2021 BioMed Central BMC
Subjects:	Aged Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Antibodies Antigens Antisense RNA Biosynthesis C9orf72 Protein - genetics C9orf72 Protein - metabolism Cell cycle Cell Nucleolus - genetics Cell Nucleolus - metabolism Cell Nucleolus - pathology Cytoplasm DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Ethanol Female Frontotemporal Lobar Degeneration - genetics Frontotemporal Lobar Degeneration - metabolism Frontotemporal Lobar Degeneration - pathology Humans Immunohistochemistry Male Medical research Medicine, Experimental Middle Aged Motor Neurons - metabolism Motor Neurons - pathology Neurons Pathogenesis Pathology Proteins RNA - genetics Sex Factors Spinal cord Spinal Cord - pathology Atlanta Georgia Sudan
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2051-5960 2051-5960
DOI:	10.1186/s40478-021-01125-6