Loss of neurons is a key macroscopic feature that unites all neurodegenerative diseases including Huntington’s disease (HD) and Amyotrophic lateral sclerosis (ALS). These diseases affect distinct neuronal subtypes, e.g. striatum and cortex in HD and motor neurons in ALS. However, it is clear that common molecular mechanisms may underlie pathogenic features of each disease. Currently, there is no disease modifying treatment for HD or ALS. It is critical to elucidate the specific mechanisms leading to pathogenesis.
A single gene mutation, a CAG repeat expansion within the HD gene, causes HD. In contrast, 90% of all cases of ALS are sporadic and of the known gene mutations that cause familial versions of the disease, there are several contributing genes with the C9orf72 mutation accounting for the majority. Ultimately, in both diseases, numerous cellular functions are impacted including protein homeostasis, transcriptional regulation, cellular signaling, and bioenergetics; causing dysfunction and cell death.
A shared pathogenic feature which seems, at least in part, to be causative is the dysregulation of gene expression. In order to study this and other pathogenic mechanisms, we utilized patient-derived induced pluripotent stem cells (iPSCs) from both HD and ALS subjects and differentiated them into relevant cell types. For HD, mixed neural cells directed towards a striatal fate and brain endothelial cells (BECs) were generated, and motor neurons generated from ALS subjects. These cells were compared to lines generated from unaffected, healthy subjects for unbiased “omics” analysis to identify potential mechanisms underlying neurodegeneration.
My data suggest that mutant Huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the expanded polyglutamine repeats over time. Additionally, I provide the first iPSC-derived barrier-forming EC model for a neurodegenerative disease to date, demonstrating specific barrier defects that may underlie crucial aspects of HD pathology.
RNA-seq analysis was also performed for iPSC-derived ALS motor neurons as a component of a large consortium effort to identify cell-based signatures. Alternative splicing and mislocalization of RNA binding proteins (RBPs) appears to also contribute to ALS pathogenesis, and here we identify RBPs that could contribute to this aberrant alternative splicing and dysregulated RNA biology.