2012 Theses Doctoral

The ALS Genes TDP-43 and FUS/TLS Regulate a Common Pathway in the Nervous System of Drosophila Melanogaster

Brent, Jonathan Robert

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the dysfunction and death of motor neurons. Patients afflicted with this condition commonly experiences muscle weakness that progresses to generalized paralysis. Although most ALS cases are sporadic, mutations in several human genes of divergent molecular function have been linked to the development of ALS. Recently, two new ALS genes, TDP-43 and FUS, were identified that have structural similarities suggesting that they may function in a common process. TDP-43 and FUS have both been implicated in a number of cellular functions, including the regulation of splicing, transcription, and microRNA processing. The work in this thesis includes studies that identified roles for TDP-43 and FUS in the health and function of the nervous system of Drosophila melanogaster. Genetic and biochemical studies were used to define the molecular relationships between TDP-43 and FUS, placing TDP-43 upstream of FUS in a common pathway that is important for the function and health of the nervous system. The finding that TDP-43 and FUS interact suggests that they regulate a common disease pathway that is disrupted in ALS and that therapeutic intervention in this pathway may ameliorate many of the symptoms of the disease.