|Education||MS, Georgetown University|
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is one of the most common neurodegenerative diseases. Rapid, progressive loss of upper and lower motor neurons in the corticospinal tract and brainstem invariably results in widespread muscle wasting and paralysis. With rare exceptions, patients die due to respiratory failure within 2-5 years after diagnosis.
A number of genes have been linked to ALS, but they only account for a small proportion of cases. In 2011, two independent groups identified an intronic GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene that is the most common genetic cause of ALS as well as frontotemporal dementia known to date. Normal, healthy individuals typically carry between 5-20 (GGGGCC)n repeats, whereas C9ORF72 ALS patients can have hundreds or even thousands of repeats. Repeat expansions are predicted to cause pathology by three potential mechanisms: 1) haploinsufficiency, 2) RNA-mediated toxicity, and 3) repeat-associated non-ATG (RAN) translation.
Much of the work on C9ORF72 ALS has focused on neurons. However, glial cells are also known to play an important role in ALS by modulating disease onset and progression. In particular, astrocytes often exhibit altered structure and functionality under disease conditions. My project aims to determine if the C9ORF72 mutation induces a pathological phenotype in astrocytes and, if so, by what mechanism(s) it may contribute to neurodegeneration in ALS. To more faithfully recapitulate processes occurring in patients, we have generated a bank of induced pluripotent stem (iPS) cells derived from patient fibroblasts that we can then differentiate into different neural cell types, including astrocytes. I am assessing these iPS-derived astrocytes for the three previously mentioned mechanisms by which intronic repeat expansions can cause disease.