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Kathleen Cunningham

Class 2013
Education BA, Dartmouth College
Email kcunni13@jhmi.edu
Mentor

Dr. Tom Lloyd

Research Interests

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease (ND) involving loss of motor neuron function and integrity, ultimately leading to paralysis and death. Recently, a (GGGGCC)n hexanucleotide repeat expansion (HRE) in the first intron of the gene c9orf72 (chromosome 9 open reading frame 72) was identified as the most common genetic cause of ALS (c9-ALS). c9-ALS accounts for ~50% of familial and ~10% of sporadic cases of ALS. The (GGGGCC)n HRE is proposed to cause neuronal toxicity by two major mechanisms: 1) the HRE mRNA transcripts bind and sequester RNA-binding proteins and 2) repeat-associated, non-ATG translation (RANT) of the HRE generates toxic dipeptides. In support of the first mechanism, HRE mRNA foci form in patient-derived iPS neurons; in support of RANT, dipeptide aggregates are found in patient neurons and in iPS neurons derived from c9-ALS patients.

Several Drosophila models have been shown to recapitulate key features of the disease and therefore enable us to study its mechanism. In our lab, we use a fly model of c9-ALS caused by expressing (GGGGCC)30 under the control of an eye-specific Gal4 driver. Consistent with the findings in c9-ALS patients, we observe p62/ubiquitin-positive aggregates, TDP-43 mislocalization and aggregation, and dipeptide repeat expression in our fly model. My preliminary data suggest that genetically and pharmacologically alleviating proteotoxic stress strongly suppresses neurodegeneration caused by HRE expression in the Drosophila eye. Together, these data suggest that p62-mediated autophagy of ubiquitinated aggregates plays an important role in HRE-mediated toxicity. The goal of this study is to understand the role of protein quality control pathways in the pathogenesis of c9-ALS.

Publications

Zhang K*, Donnelly CJ*, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE*, Rothstein JD* (2015) The C9ORF72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. doi: 10.1038/nature14973. PMID:26308891