--- title: "Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement" id: "8148" type: "study" slug: "sa000068" published_at: "2025-04-24T21:12:37+00:00" modified_at: "2026-03-26T16:38:35+00:00" url: "https://dss.niagads.org/studies/sa000068/" markdown_url: "https://dss.niagads.org/studies/sa000068.md" excerpt: "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..." --- ## 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. ## PI Kelly L. Williams, Ph.D. *Macquarie University* Natalie Grima, Ph.D. *Macquarie University* ## Associated Datasets - [NG00178 - Multi-brain region mRNA-seq of sporadic ALS patients with pTDP-43 pathological staging](https://dss.niagads.org/datasets/ng00178/) Post-mortem fresh-frozen brain tissue was obtained for 22 sporadic amyotrophic lateral sclerosis (ALS) cases and 11 neurologically healthy control participants from Sydney Brain Bank and the New South Wales Brain… [Learn more](https://dss.niagads.org/datasets/ng00178/) ## Associated Sample Sets - [snd10119 - ALS mRNA Sequencing](https://dss.niagads.org/sample-sets/snd10119/) This data includes 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions were examined (n=165 samples total): motor cortex (pTDP-43 inclusions… [Learn more](https://dss.niagads.org/sample-sets/snd10119/) ## Cohorts - [New South Wales Brain Tissue Resource Centre](https://dss.niagads.org/cohorts/new-south-wales-brain-tissue-resource-centre/) The New South Wales Brain Tissue Resource Centre (NSWBTRC) at the University of Sydney collects and characterizes human brain and spinal cord tissue with a focus on alcohol disorders, mental… [Learn more](https://dss.niagads.org/cohorts/new-south-wales-brain-tissue-resource-centre/) - [Sydney Brain Bank](https://dss.niagads.org/cohorts/sydney-brain-bank/) The Sydney Brain Bank (SBB) at Neuroscience Research Australia collects and characterizes human brain and spinal cord tissue from healthy aged donors and those with neurodegenerative conditions. Donors with motor… [Learn more](https://dss.niagads.org/cohorts/sydney-brain-bank/) ## Grants 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. ## Acknowledgement ### Acknowledgment statement for any data distributed by NIAGADS: Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging. ### For investigators using Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement data: Post-mortem tissues were received from the Sydney Brain Bank at Neuroscience Research Australia and the New South Wales Brain Tissue Resource Centre at the University of Sydney. Tissues samples were collected by Heather McCann and Julia Stevens. pTDP-43 pathological stage classification of post-mortem brain tissues including post-mortem diagnosis was performed by Claire E. Shephard. Dominic B. Rowe and Matthew C. Kiernan ascertained patients and clinical data. Genetic screening and extraction of RNA from post-mortem brain tissues was performed by Natalie Grima. Funding to support this project was acquired by Kelly L. Williams, Ian P. Blair and Natalie Grima. We sincerely thank the study participants for their invaluable contribution to this study. ## 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](https://pubmed.ncbi.nlm.nih.gov/40275359/)