Retrotransposon Reactivation in Neurodegenerative Disease
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that causes complete paralysis and eventual death from the rapid and progressive loss of motor neurons. While a number of inherited mutations have been identified as causing ALS, the vast majority of patients have no known causal mutation or family history of disease. My lab has recently partnered with the NYGC ALS Consortium to undertake a large-scale integrated analysis of molecular alterations in ALS patients. The scale of this dataset allowed for a clean separation of ALS patients into a small set of distinct subtypes. One of these ALS subtypes involves the reactivation of endogenous retrotransposons, viral-like genomic parasites that normally lay dormant in the genome. This proposed study will develop novel machine learning software to systematically identify the genetic factors and molecular mechanisms that lead to motor neuron cell death, with a particular focus on retrotransposon reactivation.
Results & Resources
The first release from the Gale-Hammell Lab and the NYGC ALS Consortium provided an overview of the transcriptional landscapes of motor and frontal cortex samples from ALS patients (Tam et al. 2019). In this study, they found three distinct molecular subtypes within ALS that were marked by elevation of: oxidative stress pathways, neuroinflammatory pathways, and retrotransposons. They also showed that retrotransposon de-silencing was a direct consequence of TDP-43 pathology. Ongoing work is exploring (1) how retrotransposon activity contributes to ALS, (2) whether ALS subtype markers can be detected in peripheral tissues and sera, and (3) how genetic factors intersect with other factors to contribute to these molecularly defined ALS pathways.
A companion review article from this group describes the larger impacts of retrotransposon activity in ALS and other neurodegenerative diseases (Tam, Ostrow, and Gale-Hammell, 2019).