Project description:Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls.

2007-09-26 | E-GEOD-833 | biostudies-arrayexpress

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia [eCLIP]

Project description:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). Together these results demonstrate that at least three distinct molecular signatures contribute to ALS disease. While multiple dysregulated components and pathways comprising these clusters have previously been implicated in ALS pathogenesis, unbiased analysis of this large survey demonstrated that sporadic ALS patient tissues can be segregated into distinct molecular subsets.

2019-09-20 | GSE122648 | GEO

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia [shRNA]

2019-09-20 | GSE122647 | GEO

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia [motor cortex]

2019-09-20 | GSE122649 | GEO

CREB3 gain of functions variants protect against ALS

Project description:Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal single cell RNA-seq data on male Sod1G86R mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3R119G (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.

2025-04-02 | GSE291695 | GEO

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