Nucleolar stress in C9orf72 and sporadic ALS spinal motor neurons precedes TDP-43 mislocalization
| Autor: | John Ravits, Sandra Nguyen, Ringo Leung, Olubankole Aladesuyi Arogundade, María Jesús Delgado Rodríguez, Danielle Wainio |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Pathology medicine.medical_specialty Nucleolus Clinical Sciences Biology Neurodegenerative lcsh:RC346-429 Pathology and Forensic Medicine Cellular and Molecular Neuroscience Sex Factors Rare Diseases C9orf72 mental disorders Sense (molecular biology) medicine Acquired Cognitive Impairment Humans Amyotrophic lateral sclerosis lcsh:Neurology. Diseases of the nervous system Aged Motor Neurons C9orf72 Protein Research Amyotrophic Lateral Sclerosis Neurosciences RNA Frontotemporal lobar degeneration Middle Aged Spinal cord medicine.disease Immunohistochemistry Antisense RNA Brain Disorders DNA-Binding Proteins Frontotemporal Dementia (FTD) medicine.anatomical_structure Spinal Cord Neurological Female Dementia Neurology (clinical) Biochemistry and Cell Biology Frontotemporal Lobar Degeneration ALS Cell Nucleolus |
| Zdroj: | Acta neuropathologica communications, vol 9, iss 1 Acta Neuropathologica Communications, Vol 9, Iss 1, Pp 1-16 (2021) Acta Neuropathologica Communications |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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