Elucidating RNA metabolism changes underlying the progressive neural cell biology of ALS

Growing evidence implicates abnormal RNA metabolism as a contributing factor to the pathobiology of amyotrophic lateral sclerosis (ALS), yet understanding remains limited in direct context of the human neurodegenerative condition. Addressing this is expected to identify new disease mechanisms and therapeutic targets. Work in the Sibley lab is integrating traditional and single-nuclei RNA sequencing to elucidate transcriptome-wide changes to RNA metabolism in clinically relevant post-mortem brain tissue and human induced pluripotent stem cell (hiPSC) models of ALS. Mechanistic follow-up of prioritised events will then use established molecular biology, functional genomics and systems biology methods within hiPSC models. Key goals will be to:

• Define RNA metabolism changes in direct context of human ALS neuropathology: Molecules and networks will be characterised at region, cell and pseudotemporal resolution.
• Mechanistically dissect key RNA metabolism changes causing neural cell dysfunction: Priority will be understanding cause and consequence of non-canonical splicing patterns we have observed in ALS, and identifying intrinsic master regulators driving our well-defined transcriptome signatures of motor neuron neurodegeneration.
• Understand how familial ALS genetics converge on selective motor neuron vulnerability: Meta-analysing transcriptomes of perturbed cells will functionally cluster familial ALS genes by their induced cellular phenotypes.

Taken together, the findings will provide penetrating insights into basic neural cell dynamics relevant to ALS initiation and progression.