Integrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Amyotrophic Lateral Sclerosis (ALS) is characterized by motor neuron degeneration and TDP-43 proteinopathy in most cases.
• Disease heterogeneity and limited access to motor neurons hinder understanding of ALS pathomechanisms.
• Human induced pluripotent stem cell-derived motor neurons (iPSMNs) provide a valuable model, but previous studies used small cohorts.

Purpose of the Study:

• To establish a comprehensive compendium of iPSMNs and post-mortem spinal cord samples for ALS research.
• To identify robust molecular alterations and pathomechanisms in ALS using large-scale data.
• To investigate the role of p53 signaling and its relationship with TDP-43 in ALS.

Main Methods:

• Compiled a large dataset of 429 iPSMNs from 15 datasets and 271 post-mortem spinal cord samples.
• Applied reproducible bioinformatic workflows to analyze genetic and molecular data.
• Investigated the impact of TDP-43 depletion on p53 activation in neuronal models.

Main Results:

• Identified robust upregulation of p53 signaling in both iPSMNs and post-mortem spinal cord samples from ALS patients.
• Observed varying degrees of p53 activation depending on specific genetic mutations (C9orf72, SOD1, FUS).
• Demonstrated that TDP-43 depletion potentiates p53 activation, functionally linking these factors in ALS pathogenesis.
• Found enrichment of splicing alterations, somatic mutations, and gene fusions in ALS iPSMNs and post-mortem tissues, suggesting a role in DNA damage response.

Conclusions:

• p53 signaling is a key pathway upregulated in Amyotrophic Lateral Sclerosis (ALS).
• TDP-43 depletion is functionally linked to p53 activation, a critical event in ALS.
• Genetic alterations and DNA damage responses may contribute to ALS pathology, highlighting potential therapeutic targets.