Description

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We conducted a comprehensive bioinformatic analysis of transcriptome alterations, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles.

Principal Investigators

Kelly L. Williams, Ph.D.
Macquarie University

Natalie Grima, Ph.D.
Macquarie University

 

Funding Sources

This work was funded by NHMRC (Ideas Grant 2011120 to KLW, Investigator Grant 1176913 to IPB), FightMND (Angie Cunningham PhD Scholarship and Project Grant-In-Aid Award to NG and IPB, Discovery Grant to NG and KLW), and Motor Neurone Disease Research Australia (Grant-in-Aid to KLW). The Sydney Brain Bank is supported by Neuroscience Research Australia and a special gift in memory of Jim Raftos from the Shaw family. The New South Wales Brain Tissue Resource Centre is supported by the National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number R28AA012725.

 

Publications

  • Grima N. Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement. Molecular neurodegeneration. 2025 Apr 25. PubMed link