Acta Neuropathologica: Mitochondrial bioeneral energy defects in C9orf72 amyotrophic lateral sclerosis motor neurons lead to axon stabilization disorders

Amyotrophic lateral sclerosis (ALS) is an incurable, rapidly progressing, deadly neurodegenerative disease characterized by the absence of upper and lower motor neurons (MNs) and their axons up to 1 meter long.
are the only species affected by the exudable ALS.
about 10-20% of ALS cases are familial, with C9orf72 heterinotide repeat sequence amplification mutations being the most common cause.
is no significant difference between familyal ALS clinically and pathologically and exudable ALS, and this finding also supports the study of single-gene pathogenesies to better understand common pathological mechanisms.
Thus, the human-induced erythnic stem cell (iPSC)-derived MN experimental platform, combined with the isogen control system of paired gene editing, provides a powerful way to identify both early disease-driven mechanisms and establish causal relationships between given mutations and esotypes.
although alS clinical esoplots including high metabolism and lipid abnormalities are widely recognized, there is limited understanding of its underlying mechanisms and/or relationship to MN metabolic states.
Compared with astrocytes, neurons rely mainly on mitochondrial oxidation phosphate, plus extra-long MN axons, which are 20,000 times longer than their cystic diameters, indicating that MN is particularly prone to metabolic defects in the critical process of maintaining the form and function of axons: axon steady-state dysfunction.
maintenance of axon function is a process of high energy consumption, which raises the question of whether MN cytocytology is disturbed in ALS and whether its recovery promotes axon repair.
to solve this problem, the study tested cells and molecules on induced erypotent stem cell line and patient autopsy samples from multiple patient sources, which contained the most common ALS-induced mutation gene C9orf72.
using pairing mutations and isometric amplification to correct the control, we found that C9orf72 MNs axons were shorter, rapid axon transport of mitochondrial cargo was impaired, and mitochondrial biomass function was altered.
RNA sequencing revealed a decrease in gene expression of mitochondrial-encoded electron transfer chain transcripts, and neuropathological analysis of C9orf72-ALS post-mortem tissue importantly confirmed the selectivity of mitochondrial coding transcripts in the abdominal spinal spinal cord MNs, but not in the corresponding back-angle sensory neurons, and its findings were reflected at protein levels.
number of copies of mitochondrial DNA did not change in introphy or in posthumous tissue.
genetic action on C9orf72 MNs mitochondrial organisms corrected bioenear deficiencies and saved shaft protrusion length and transport esomor.
, the data in this paper show that the loss of mitochondrial function is a key medium for C9orf72 amyotrophic lateral sclerosis axon dysfunction.
MN bioenearity is sufficient to restore the steady state of the axon, thus opening up new potential therapeutic strategies for ALS targeting mitochondrial function.
Mehta, A.R., Gregory, J.M., Dando, O. et al. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol (2021). MedSci Original Source: MedSci Original Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Mets Medicine" or "Source: MedSci Original" are owned by Mets Medicine and are not authorized to be reproduced by any media, website or individual, and are authorized to be reproduced with the words "Source: Mets Medicine".
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