Early MATR3 loss and distinct neurodegenerative molecular signatures precede the onset of neuropathology in motor neurons and Purkinje cells of MATR3 S85C knock-in mouse model of ALS
- 1The Hospital for Sick Children
Abstract
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, leading to progressive muscle weakness and motor impairment. Growing evidence indicates that cerebellar Purkinje cells, which play a central role in motor coordination, are also affected in ALS. However, it is unclear whether the molecular events that initiate neurodegeneration in these ALS-relevant motor-controlling neurons are shared or distinct. Here, we used a MATR3 S85C knock-in (KI) mouse model of early-stage ALS with stage-specific motor phenotypes and selective vulnerability of motor neurons and Purkinje cells to decipher the molecular events underlying neurodegeneration in these two neuronal populations. We found that a profound reduction in detectable MATR3 S85C immunoreactivity (hereafter referred to as MATR3 loss) in both motor neurons and Purkinje cells precedes the onset of motor dysfunction and neuropathology, implicating MATR3 loss as the earliest detectable molecular event. Our bulk cerebellar RNA profiling and motor neuron-specific RNA profiling data at the onset of MATR3 loss revealed distinct molecular signatures. In the cerebellum, Ngfr expression emerged in Purkinje cells before the onset of neuronal loss and remained elevated throughout the disease course. This increase was accompanied by activation of the JNK-mediated cell death pathway. In the motor neurons, elevated Fgf21 and integrated stress response (ISR) gene expression were the first to be observed and persisted throughout disease progression, consistent with previous findings in SOD1 mouse models. Our findings provide mechanistic insights into the initiation of neurodegeneration in ALS-relevant motor-controlling neurons and implicate potential neuron type-specific targets for future therapeutics.
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BibTeX
@misc{maksimovic2026early,
title = {{Early MATR3 loss and distinct neurodegenerative molecular signatures precede the onset of neuropathology in motor neurons and Purkinje cells of MATR3 S85C knock-in mouse model of ALS}},
author = {K. Maksimovic and R. Majji and J. R. Santos and C. Chan and A. Zelaya and J. Lee and M. Dias and O. B. Gluscencova and M. M. M. Youssef and S. Kim and T. Noronha and C. Lai and Y. Fan and M. N. Metri and J. You and C. S. Kao and L.-Y. Wang and J. L. Lefebvre and M. D. Wilson and H. K. Yalamanchili and J. Park},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.747343},
url = {https://www.biorxiv.org/content/10.64898/2026.08.26.747343v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Early MATR3 loss and distinct neurodegenerative molecular signatures precede the onset of neuropathology in motor neurons and Purkinje cells of MATR3 S85C knock-in mouse model of ALS
AU - K. Maksimovic
AU - R. Majji
AU - J. R. Santos
AU - C. Chan
AU - A. Zelaya
AU - J. Lee
AU - M. Dias
AU - O. B. Gluscencova
AU - M. M. M. Youssef
AU - S. Kim
AU - T. Noronha
AU - C. Lai
AU - Y. Fan
AU - M. N. Metri
AU - J. You
AU - C. S. Kao
AU - L.-Y. Wang
AU - J. L. Lefebvre
AU - M. D. Wilson
AU - H. K. Yalamanchili
AU - J. Park
PY - 2026
DA - 2026/08/26
PB - bioRxiv
DO - 10.64898/2026.08.26.747343
UR - https://www.biorxiv.org/content/10.64898/2026.08.26.747343v1
AB - Amyotrophic lateral sclerosis (ALS) is a motor neuron disease, leading to progressive muscle weakness and motor impairment. Growing evidence indicates that cerebellar Purkinje cells, which play a central role in motor coordination, are also affected in ALS. However, it is unclear whether the molecular events that initiate neurodegeneration in these ALS-relevant motor-controlling neurons are shared or distinct. Here, we used a MATR3 S85C knock-in (KI) mouse model of early-stage ALS with stage-specific motor phenotypes and selective vulnerability of motor neurons and Purkinje cells to decipher the molecular events underlying neurodegeneration in these two neuronal populations. We found that a profound reduction in detectable MATR3 S85C immunoreactivity (hereafter referred to as MATR3 loss) in both motor neurons and Purkinje cells precedes the onset of motor dysfunction and neuropathology, implicating MATR3 loss as the earliest detectable molecular event. Our bulk cerebellar RNA profiling and motor neuron-specific RNA profiling data at the onset of MATR3 loss revealed distinct molecular signatures. In the cerebellum, Ngfr expression emerged in Purkinje cells before the onset of neuronal loss and remained elevated throughout the disease course. This increase was accompanied by activation of the JNK-mediated cell death pathway. In the motor neurons, elevated Fgf21 and integrated stress response (ISR) gene expression were the first to be observed and persisted throughout disease progression, consistent with previous findings in SOD1 mouse models. Our findings provide mechanistic insights into the initiation of neurodegeneration in ALS-relevant motor-controlling neurons and implicate potential neuron type-specific targets for future therapeutics.
ER -