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“Flies in Motion — What Drosophila Can Tell Us about Neurodegenerative Disease,” presented by Daniela Zarnescu, associate professor, University of Arizona.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death and muscle atrophy. Due to the presence of disease-causing mutations and its association with pathological aggregates in 97% of ALS cases, the RNA binding protein TDP-43 has emerged as a major molecular denominator in disease.
Using a systems approach we have uncovered TDP-43 dependent synaptic deficits caused by mRNA sequestration and translation inhibition in Drosophila and patient-derived motor neurons. Overexpression of specific mRNAs sequestered by TDP-43 in insoluble aggregates restores microtubule stability and the synaptic vesicle cycle at the neuromuscular junction, which in turn mitigates locomotor deficits and increases lifespan.
Transcriptome and translatome profiling in Drosophila models further support a model whereby synaptic and metabolic genes are dysregulated in degenerating motor neurons. Indeed, mitochondrial and ATP production deficits appear to be compensated by increased glycolytic input, which mitigates ALS phenotypes across multiple models. Collectively, our “fly to man” approach indicate that RNA based mechanisms can explain key functional deficits in motor neuron disease and inform therapeutic strategies.
Light refreshments will be served.