James Orengo Lab

The Orengo Lab studies motor neuron degeneration using single gene mutation models to determine the common underpinnings involved in triggering this degeneration. Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia due to cerebellar degeneration. While the hallmark of SCA1 is loss of motor coordination or ataxia, as the disease progresses premature death occurs from complications secondary to bulbar dysfunction (breathing and swallowing difficulties). SCA1 is caused by expansion of CAG repeats encoding poly-glutamines (polyQ) in ATAXIN1 (Atxn1).

Substantial effort has been invested in determining the molecular mechanism by which polyQ expanded Atxn1 leads to Purkinje cell death and cerebellar degeneration. This is largely due to the fact that Purkinje cells seem to be the first and hardest hit neurons in SCA1. However, loss of Purkinje cells alone does not account for the respiratory failure and swallowing dysfunction, prompting fundamental questions about the pathogenic mechanism of bulbar dysfunction. We hypothesize that degeneration of motor neurons is the main driver of premature death in SCA1. Using mouse models for SCA1 we made the exciting observation that these mice display overt signs of motor neuron degeneration that correlates with the development of muscle wasting and bulbar dysfunction.

We further generated a novel conditional SCA1 mouse model that allows for cell-specific expression of the expanded polyQ Atxn1, and we are investigating whether expression of the toxic protein in motor neurons alone is necessary and/or sufficient to drive muscle wasting and bulbar dysfunction in SCA1. In addition, we have made several transgenic zebrafish models for SCA1 and are currently characterizing and validating these lines.