Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity - Sorbonne Université Access content directly
Journal Articles Cellular and Molecular Life Sciences Year : 2023

Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient' fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.
Fichier principal
Vignette du fichier
LefebvreOmar et al 2023.pdf (2.98 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Licence : CC BY - Attribution

Dates and versions

hal-04242330 , version 1 (14-10-2023)

Identifiers

Cite

Cynthia Lefebvre-Omar, Elise Liu, Carine Dalle, Boris Lamotte D’incamps, Stéphanie Bigou, et al.. Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity. Cellular and Molecular Life Sciences, In press, 80 (6), pp.150. ⟨10.1007/s00018-023-04797-6⟩. ⟨hal-04242330⟩
15 View
4 Download

Altmetric

Share

Gmail Facebook X LinkedIn More