Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons

Jakub Scaber; Iona Thomas-Wright; Alex J Clark; Yinyan Xu; Björn F Vahsen; Mireia Carcolé; Ruxandra Dafinca; Lucy Farrimond; Adrian M Isaacs; David L Bennett; Kevin Talbot

doi:10.1016/j.stemcr.2024.05.008

Cellular and axonal transport phenotypes due to the C9ORF72 HRE in iPSC motor and sensory neurons

Stem Cell Reports. 2024 Jul 9;19(7):957-972. doi: 10.1016/j.stemcr.2024.05.008. Epub 2024 Jun 13.

Authors

Affiliations

¹ Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK. Electronic address: jakub.scaber@ndcn.ox.ac.uk.
² Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK.
³ Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK; Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Queen Mary University, E1 2AT London, UK.
⁴ Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK; Chinese Academy of Medical Sciences (CAMS), CAMS Oxford Institute (COI), Nuffield Department of Medicine, University of Oxford, OX3 7FZ Oxford, UK.
⁵ UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, WCIN 3BG London, UK.
⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK.
⁷ Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, OX1 3QU Oxford, UK. Electronic address: kevin.talbot@ndcn.ox.ac.uk.

Abstract

Induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from patients with amyotrophic lateral sclerosis (ALS) and the C9ORF72 hexanucleotide repeat expansion (HRE) have multiple cellular phenotypes, but which of these accurately reflect the biology underlying the cell-specific vulnerability of ALS is uncertain. We therefore compared phenotypes due to the C9ORF72 HRE in MNs with sensory neurons (SNs), which are relatively spared in ALS. The iPSC models were able to partially reproduce the differential gene expression seen between adult SNs and MNs. We demonstrated that the typical hallmarks of C9ORF72-ALS, including RNA foci and dipeptide formation, as well as specific axonal transport defects, occurred equally in MNs and SNs, suggesting that these in vitro phenotypes are not sufficient to explain the cell-type selectivity of ALS in isolation.

Keywords: amyotrophic lateral sclerosis; induced pluripotent stem cells; motor neuron; selective vulnerability; sensory neuron.

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Axonal Transport*
C9orf72 Protein* / genetics
C9orf72 Protein* / metabolism
DNA Repeat Expansion* / genetics
Humans
Induced Pluripotent Stem Cells* / cytology
Induced Pluripotent Stem Cells* / metabolism
Motor Neurons* / metabolism
Phenotype*
Sensory Receptor Cells* / metabolism

Substances

C9orf72 Protein
C9orf72 protein, human