PMID- 37184603
OWN - NLM
STAT- MEDLINE
DCOM- 20230517
LR  - 20230619
IS  - 1420-9071 (Electronic)
IS  - 1420-682X (Print)
IS  - 1420-682X (Linking)
VI  - 80
IP  - 6
DP  - 2023 May 15
TI  - Neurofilament accumulations in amyotrophic lateral sclerosis patients' motor 
      neurons impair axonal initial segment integrity.
PG  - 150
LID - 10.1007/s00018-023-04797-6 [doi]
LID - 150
AB  - 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.
CI  - (c) 2023. The Author(s).
FAU - Lefebvre-Omar, Cynthia
AU  - Lefebvre-Omar C
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Liu, Elise
AU  - Liu E
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Dalle, Carine
AU  - Dalle C
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - d'Incamps, Boris Lamotte
AU  - d'Incamps BL
AD  - Universite Paris-Cite, CNRS, Saints-Peres Paris Institute for the Neurosciences, 
      Paris, France.
FAU - Bigou, Stephanie
AU  - Bigou S
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Daube, Clement
AU  - Daube C
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Karpf, Lea
AU  - Karpf L
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Davenne, Marc
AU  - Davenne M
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Robil, Noemie
AU  - Robil N
AD  - GenoSplice Technology, Paris, France.
FAU - Jost Mousseau, Coline
AU  - Jost Mousseau C
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Blanchard, Stephane
AU  - Blanchard S
AD  - Institut Pasteur, INSERM U1115, Unite Biotherapies pour les Maladies 
      Neurodegeneratives, Paris, France.
FAU - Tournaire, Guillaume
AU  - Tournaire G
AD  - Institut Pasteur, INSERM U1115, Unite Biotherapies pour les Maladies 
      Neurodegeneratives, Paris, France.
FAU - Nicaise, Charles
AU  - Nicaise C
AD  - URPhyM, NARILIS, Universite de Namur, Namur, Belgium.
FAU - Salachas, Francois
AU  - Salachas F
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
AD  - Departement de Neurologie, Assistance Publique Hopitaux de Paris (APHP), Centre 
      de Reference SLA Ile de France, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Lacomblez, Lucette
AU  - Lacomblez L
AD  - Departement de Neurologie, Assistance Publique Hopitaux de Paris (APHP), Centre 
      de Reference SLA Ile de France, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Seilhean, Danielle
AU  - Seilhean D
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
AD  - Departement de Neuropathologie, AP-HP, Hopital de la Pitie-Salpetriere, Paris, 
      France.
FAU - Lobsiger, Christian S
AU  - Lobsiger CS
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Millecamps, Stephanie
AU  - Millecamps S
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Boillee, Severine
AU  - Boillee S
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France.
FAU - Bohl, Delphine
AU  - Bohl D
AUID- ORCID: 0000-0001-8262-5642
AD  - Sorbonne Universite, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, 
      AP-HP, Hopital de la Pitie-Salpetriere, Paris, France. 
      delphine.bohl@icm-institute.org.
LA  - eng
GR  - 16465/AFM-Telethon/
GR  - EQU202103012581/FRM/
GR  - ANR-10-LABX-73/Labex Revive/
GR  - ALS-iPSC/AAP10/Fondation Thierry Latran/
PT  - Journal Article
DEP - 20230515
PL  - Switzerland
TA  - Cell Mol Life Sci
JT  - Cellular and molecular life sciences : CMLS
JID - 9705402
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
RN  - 0 (C9orf72 Protein)
SB  - IM
MH  - Humans
MH  - *Amyotrophic Lateral Sclerosis/genetics/pathology
MH  - Intermediate Filaments
MH  - Superoxide Dismutase-1/genetics
MH  - C9orf72 Protein/genetics
MH  - Motor Neurons/pathology
PMC - PMC10185656
OTO - NOTNLM
OT  - Amyotrophic lateral sclerosis
OT  - Axonal initial segment
OT  - Degeneration
OT  - Human induced pluripotent stem cells
OT  - Motoneurons
OT  - Neurofilaments
COIS- The authors declare that they have no competing interests.
EDAT- 2023/05/15 13:06
MHDA- 2023/05/17 06:42
PMCR- 2023/05/15
CRDT- 2023/05/15 11:05
PHST- 2022/11/04 00:00 [received]
PHST- 2023/05/03 00:00 [accepted]
PHST- 2023/04/24 00:00 [revised]
PHST- 2023/05/17 06:42 [medline]
PHST- 2023/05/15 13:06 [pubmed]
PHST- 2023/05/15 11:05 [entrez]
PHST- 2023/05/15 00:00 [pmc-release]
AID - 10.1007/s00018-023-04797-6 [pii]
AID - 4797 [pii]
AID - 10.1007/s00018-023-04797-6 [doi]
PST - epublish
SO  - Cell Mol Life Sci. 2023 May 15;80(6):150. doi: 10.1007/s00018-023-04797-6.