Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS
- 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
Abstract
Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72-related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.
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BibTeX
@misc{aliya2026temporal,
title = {{Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS}},
author = {B. Aliya and S. Liu and A. Mansfield and S. X. Yao and S. Mouhi and S. S. Wariyar and J. S. Tenkorang and N. E. Smith and M. Chung and A. J. R. Yu and T. Pio and N. E. J. Smith and S. H. Zhu and A. N. Trautwig and J. Parameswaran and L. Yin and C. M. Watson and Brain Organoid Hub and J. Jiang and N. T. Seyfried and Z. T. McEachin and B. Yao and J. Andersen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.13.755334},
url = {https://www.biorxiv.org/content/10.64898/2026.10.13.755334v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Temporal RNA splicing dysregulation in a human multicellular model of C9orf72 ALS
AU - B. Aliya
AU - S. Liu
AU - A. Mansfield
AU - S. X. Yao
AU - S. Mouhi
AU - S. S. Wariyar
AU - J. S. Tenkorang
AU - N. E. Smith
AU - M. Chung
AU - A. J. R. Yu
AU - T. Pio
AU - N. E. J. Smith
AU - S. H. Zhu
AU - A. N. Trautwig
AU - J. Parameswaran
AU - L. Yin
AU - C. M. Watson
AU - Brain Organoid Hub
AU - J. Jiang
AU - N. T. Seyfried
AU - Z. T. McEachin
AU - B. Yao
AU - J. Andersen
PY - 2026
DA - 2026/10/13
PB - bioRxiv
DO - 10.64898/2026.10.13.755334
UR - https://www.biorxiv.org/content/10.64898/2026.10.13.755334v1
AB - Amyotrophic lateral sclerosis (ALS) is a complex and heterogenous disease, comprising of familial and sporadic forms, numerous genetic mutations, and a wide range of affected cell types and proposed dysregulated processes. While the usage of in vitro cell cultures, mouse models, and postmortem patient tissue have advanced our understanding of ALS disease mechanisms, the temporal progression of the disease and how early molecular changes evolve remain poorly understood. Here, we establish human spinal cord organoids (hSpO) derived from C9orf72 patient induced pluripotent stem cells (C9-ALS hiPSCs) as a platform to model longitudinal changes across the disease trajectory. We show that C9-ALS hSpO recapitulate hallmark C9orf72-related pathologies, increased cell death, and progressive neuronal dysfunction. We further identify RNA splicing dysregulation as an early and persistent feature of C9-ALS, with splicing signatures in hSpO closely mirroring those observed in postmortem patient tissue. Finally, prediction of RNA binding proteins (RBPs) that induce early splicing changes in C9-ALS reveals signatures consistent with a broad RBP network dysfunction. Together, this work establishes hSpO as an in vitro system for investigating early disease mechanisms of ALS in a human multicellular context and highlights dysregulated events that precede cell death.
ER -