FRIDAY, Jan. 11 (HealthDay News) -- Using a Drosophila fly model of Huntington's disease, researchers have discovered that increased neurotransmission caused by the abnormal huntingtin protein leads to neuronal degeneration long before huntingtin aggregates accumulate in neurons, according to an article published in the Jan. 10 issue of Neuron.
Eliana Romero, of the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, and colleagues used a novel full-length Drosophila Huntington's disease model to investigate the effect of expanded, full-length huntingtin on synaptic transmission.
The researchers showed that the expanded full-length huntingtin protein resulted in behavioral, neurodegenerative and electrophysiological abnormalities. These changes appeared to be due to a Ca2+-dependent increase in neurotransmitter release. Notably, these changes occurred early in the development of disease, before cleaved huntingtin accumulates in the nuclei of neurons.
"The increased synaptic transmission phenotype exerted by full-length huntingtin likely represents a mechanism of pathogenesis taking place at early stages of disease progression. In later stages, cleavage of huntingtin would compound the toxic effects of the full-length protein with fast axonal transport impairments and transcriptional dysregulation caused by N-terminal fragments. These findings point to increased synaptic transmission as a therapeutic target with the potential of delaying Huntington's disease onset, and thus likely impacting disease progression," the authors write.
Abstract
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