Investigating Motor Neuron Disease in Spinocerebellar Ataxia, Type1

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Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia due to cerebellar degeneration, followed by progressive degeneration and premature death. Substantial effort has been invested in determining the molecular mechanisms that lead to cerebellar degeneration. This is largely due to the fact that impairment of these neurons leads to the first symptoms identified in SCA1 patients. However, loss of cerebellar neurons alone does not account for the muscle weakness and respiratory failure, which characterize SCA1 progression, and promote premature death. This knowledge gap prompts fundamental questions about the pathogenic mechanism of premature death. SCA1 is caused by the expansion of CAG repeats encoding polyglutamines (polyQ) in the ATAXIN1 (ATXN1) protein. The polyQ ATXN1 accumulates in neurons forming nuclear aggregates ultimately leading to neuronal cell death. Of particular interest to the Orengo lab is the role motor neurons play in SCA1. These neurons control skeletal muscle activity, and when diseased, lead to skeletal muscle wasting, weakness, breathing dysfunction, swallowing difficulties and an inability to safely clear the airway, all of which predispose to respiratory complications leading to premature death. Dr. Orengo and his team hypothesize that motor neuron dysfunction in SCA1 is the main driver of premature death and that the mechanisms leading to motor neuron degeneration in SCA1 are different than those involved in cerebellar neuron degeneration. This distinction may be critical in the development of novel therapeutics that address other affected cell types than just cerebellar neurons. Using a cadre of SCA1 mouse models, the Orengo lab will be able to selectively turn on or off the expression of toxic polyQ ATXN1 in motor neurons and assess the molecular and behavioral changes that follow. Specifically, the goals of this proposal are the following. (1) Assess whether expression of polyQ ATXN1 in motor neurons is necessary for premature death in a conditional mouse model of SCA1. (2) Determine the earliest, mid and late transcriptomic changes in motor neurons secondary to autonomous and non-cell-autonomous polyQ ATXN1 expression. This investigation utilizes an innovative in vivo approach, with dissociated motor neurons from the spinal cords of mice, sorting their nuclei based on a fluorescent marker, and then deep sequencing the mRNA molecules present. (3) Explore the role of the master transcriptional regulator Mdfi in a SCA1 mouse model and ascertain its affect upon the JNK/Jun signaling cascade. Dr. Orengo’s proposed study is significant because it will shed new light on the role motor neuron disease plays in SCA1, as well as what pathways are triggered within these neurons that lead to their degeneration. Understanding these mechanisms will be crucial for developing more effective therapies that address muscle weakness and premature death in SCA1 patients.