Our group seeks to better understand what causes neurodegenerative diseases, including ALS and dementia, and to identify novel therapeutic approaches for these devasting disorders. Our research integrates the study of stem cell-derived neuronal models of disease with next-generation neuropathology approaches.

Dysfunction of protein homeostasis in neurodegenerative diseases

Cells have evolved finely tuned pathways that regulate the production and degradation of proteins. Collectively, the ubiquitin-proteasome system, the autophagy-lysosomal pathway, and protein chaperones work in concert to maintain protein homeostasis (or proteostasis), and function in the removal of misfolded proteins. Disruption in any of these pathways can contribute to neural dysfunction and age-related neurodegenerative diseases. For instance, loss-of-function variants in several autophagy-related proteins are associated with familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent projects are focused on how selective autophagy cargo receptors are regulated in human pluripotent stem cells and excitatory neurons. 

The link between a repeat expansion in the genome and ALS

The most common cause of ALS, which affects motor neurons, and frontotemporal dementia (FTD) is a hexanucleotide (GGGGCC) repeat expansion within an intron of C9ORF72, which encodes a protein that likely functions in endo-lysosomal pathways. This repeat expansion is transcribed into repetitive RNAs that sequester RNA binding-proteins and undergoes non-canonical translation, in the both the sense and antisense directions, into dipeptide repeat proteins in the absence of an ATG start codon. We are working to determine how these dipeptide proteins cause cellular toxicity and contribute to disease pathogenesis using stem cells to generate the neuronal populations that are affected in disease. This research integrates a combination of transcriptomic and proteomic approaches as well as single-cell technologies to examine patient brain samples.

Applying new neuropathological approaches to examine the brain at an increased cellular resolution

A generation ago, the introduction of antibodies for immunofluorescence allowed researchers to achieve a better understanding of disease pathogenesis at a cellular level, albeit one protein at a time. Newer single-cell methods to study the cellular heterogeneity of the brain have rapidly advanced, both in the context of neurodevelopment and neurodegeneration.  We are using single-cell approaches obtain a comprehensive view of the changes across cell types (neurons and glia) in neurodegenerative diseases associated with TDP-43 pathology or alpha-synuclein pathology. For instance, we have observed that ALS/FTD-associated genes are most prominently expressed in deep-layer cortical, excitatory neurons. The generation of large patient-derived datasets allows us to generate hypotheses regarding disease mechanisms that can be validated in stem cell-based models of disease and in patient cohorts.