@article{23c82c511b804103a172befa6adc854c,
title = "Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons",
abstract = "Dysregulated neuronal excitability is a hallmark of amyotrophic lateral sclerosis (ALS). We sought to investigate how functional changes to the axon initial segment (AIS), the site of action potential generation, could impact neuronal excitability in ALS human induced pluripotent stem cell (hiPSC) motor neurons. We find that early TDP-43 and C9orf72 hiPSC motor neurons show an increase in the length of the AIS and impaired activity-dependent AIS plasticity that is linked to abnormal homeostatic regulation of neuronal activity and intrinsic hyperexcitability. In turn, these hyperactive neurons drive increased spontaneous myofiber contractions of in vitro hiPSC motor units. In contrast, late hiPSC and postmortem ALS motor neurons show AIS shortening, and hiPSC motor neurons progress to hypoexcitability. At a molecular level, aberrant expression of the AIS master scaffolding protein ankyrin-G and AIS-specific voltage-gated sodium channels mirror these dynamic changes in AIS function and excitability. Our results point toward the AIS as an important site of dysfunction in ALS motor neurons.",
keywords = "ALS, axon initial segment, C9orf72, CP: Neuroscience, fasciculations, homeostatic plasticity, human iPSC, hyperexcitability, motor neuron, motor unit, optogenetic, TDP-43",
author = "Peter Harley and Caoimhe Kerins and Ariana Gatt and Guilherme Neves and Federica Riccio and Machado, {Carolina Barcellos} and Aimee Cheesbrough and Lea R'Bibo and Juan Burrone and Ivo Lieberam",
note = "Funding Information: The authors acknowledge financial support from the Medical Research Council (grant no. MR/N025865/1) to I.L. the Wellcome Trust (Investigator award 215508/Z/19/Z), and BBSRC (grant no. BB/S000526/1) to J.B. P.H. and F.R. were supported by Wellcome Trust “Cell Therapies & Regenerative Medicine” PhD studentships (108874/Z/15/Z), C.K. was supported by Wellcome Trust “Advanced Therapies for Regenerative Medicine” PhD studentship (218461/Z/19/Z) and A.C. by a BBSRC LIDo PhD studentship (BB/M009513/1). The authors also acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas{\textquoteright} NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. The authors are also grateful to the Wellcome Trust and MRC for funding through the Human Induced Pluripotent Stem Cell Initiative (WT098503). HipSci Lines samples were collected from consented research volunteers recruited from the NIHR Cambridge BioResource through https://www.cambridgebioresource.group.cam.ac.uk/. The HipSci consortium obtained ethics approval for a revised consent (REC ref. 09/H0304/77, V3 15/03/2013), under which all data, except from the Y chromosome from males, can be made openly available (Y chromosome data can be used to de-identify men by surname matching). The authors acknowledge the Medical Research Council Center grant MR/N026063/1. This research was funded, in part, by the Wellcome Trust (215508/Z/19/Z). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. We would like to thank the London Neurodegenerative Diseases Brain Bank and Brains for Dementia Research for providing postmortem tissue. We would also like to thank Siddharthan Chandran, Bhuvaneish Selvaraj, Agnes Nishimura, and Christopher Shaw for sharing cell lines and reagents; Oliver Baker, Ieva Berzanskyte, Benjamin Compans, Vincenzo Mastrolia, and Winnie Wefelmeyer for advice on experimental techniques; and Winnie Wefelmeyer, Matthew Grubb, Benedikt Berninger, Nicolas Marichal Negrin, and Geraldine Jowett for comments on the manuscript. Conceptualization, P.H. J.B. and I.L.; methodology, P.H. C.K. A.G. F.R. A.C. C.B.M. L.R'B. J.B. and I.L.; formal analysis, P.H. and G.N.; investigation, P.H. C.K. G.N. F.R. A.C. and I.L.; writing – original draft, P.H. G.N. J.B. and I.L.; writing – review & editing, P.H. C.K. G.N. J.B. and I.L.; visualization, P.H. and I.L.; supervision, J.B. and I.L.; funding acquisition, J.B. and I.L. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: The authors acknowledge financial support from the Medical Research Council (grant no. MR/N025865/1 ) to I.L., the Wellcome Trust (Investigator award 215508/Z/19/Z ), and BBSRC (grant no. BB/S000526/1 ) to J.B. P.H. and F.R. were supported by Wellcome Trust “Cell Therapies & Regenerative Medicine” PhD studentships ( 108874/Z/15/Z ), C.K. was supported by Wellcome Trust “Advanced Therapies for Regenerative Medicine” PhD studentship ( 218461/Z/19/Z ) and A.C. by a BBSRC LIDo PhD studentship ( BB/M009513/1 ). The authors also acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy{\textquoteright}s & St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London and King{\textquoteright}s College Hospital NHS Foundation Trust. The authors are also grateful to the Wellcome Trust and MRC for funding through the Human Induced Pluripotent Stem Cell Initiative ( WT098503 ). HipSci Lines samples were collected from consented research volunteers recruited from the NIHR Cambridge BioResource through https://www.cambridgebioresource.group.cam.ac.uk/ . The HipSci consortium obtained ethics approval for a revised consent (REC ref. 09/H0304/77, V3 15/03/2013), under which all data, except from the Y chromosome from males, can be made openly available (Y chromosome data can be used to de-identify men by surname matching). The authors acknowledge the Medical Research Council Center grant MR/N026063/1 . This research was funded, in part, by the Wellcome Trust ( 215508/Z/19/Z ). For the purpose of open access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. We would like to thank the London Neurodegenerative Diseases Brain Bank and Brains for Dementia Research for providing postmortem tissue. We would also like to thank Siddharthan Chandran, Bhuvaneish Selvaraj, Agnes Nishimura, and Christopher Shaw for sharing cell lines and reagents; Oliver Baker, Ieva Berzanskyte, Benjamin Compans, Vincenzo Mastrolia, and Winnie Wefelmeyer for advice on experimental techniques; and Winnie Wefelmeyer, Matthew Grubb, Benedikt Berninger, Nicolas Marichal Negrin, and Geraldine Jowett for comments on the manuscript. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = dec,
day = "26",
doi = "10.1016/j.celrep.2023.113509",
language = "English",
volume = "42",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier BV",
number = "12",
}