Description:

As the brain is composed of distinct neuronal and glial cell-types, it requires sophisticated interactions and co-regulation to maintain healthy brain function. This cell-type specific complexity and heterogeneity are even more important under disease conditions when minor and/or local disruptions are thought to contribute to severe dysfunction and subsequent degeneration of brain cells. We recently performed snRNA sequencing analysis on brain tissue samples of patients characterized by a mutation in the C9ORF72 gene. The GGGGCC (G4C2) hexanucleotide repeat expansion in the first intron of the C9ORF72 gene is the most common genetic abnormality associated with a neurodegenerative disease spectrum that includes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD; C9-ALS/FTD). The snRNA seq analyses allowed us to explore varying aspects of cell-type specific dysfunctions in this disease spectrum, including the vulnerability to TDP-43 dysfunction of select excitatory neuron subtypes and the contribution of subsets of astrocytes to synaptic cortical neuron dysfunction. Using human iPSC cell culture models, we expanded on these human ex-vivo findings to explore mechanisms of these aberrations and assess potential new avenues for therapeutic intervention.