Major and Classification
Philosophy and Neuroscience
Faculty Mentor
John P. Walsh, Ph.D.
Department
Dornsife College of Letters, Arts and Sciences
McNair Project
“Treadmill Exercise Delays Intranuclear Protein Aggregation But Does Not Alter Motor Deficits in 140 CAG Knock-in Mouse Model of Huntington’s Disease”
Project Abstract
Huntington’s disease (HD) is a rapidly progressing autosomal dominant neurodegenerative disorder affecting 5-10 per 100,000 people worldwide. HD is characterized by primarily cortical and basal ganglia pathology. Accordingly, individuals with HD demonstrate motor impairment as well as significant mood and cognitive dysfunction and, ultimately, premature death. While HD is caused by a CAG trinucleotide repeat in exon 1 of the Huntingtin protein (Htt) on chromosome 4, the etiology is unknown. Previous studies have examined the role of intranuclear mutated Huntingtin (mHtt) aggregates in HD subjects. In order to further investigate the role of mHtt in the progression of HD, we have acquired a mouse model that expresses 140 CAG repeats in the Htt protein. This transgenic model of HD presents intranuclear inclusions of the mHtt as early as 2 months old, and provides an opportunity to compare the development of pathology in the basal ganglia with the onset of behavioral deficits. Given the role that high intensity forced exercise plays in mitochondrial function and our lab’s previous work on exercise in neural repair and plasticity, we examined its effect as a therapeutic intervention to reduce Htt aggregate development and load, relieve mitochondrial stress, and ameliorate motor, affective, and cognitive behavioral deficits. Changes in Htt aggregate pathology were assayed through immunohistochemistry. Our team found intranuclear mHtt aggregates in non-exercised HD animals as early as 2 months of age; however, these aggregates were not found in 2 month old exercised mice. These findings led us to believe that exercise retards the progression of intranuclear mHtt aggregates. Furthermore, our study used an array of behavioral tasks, which includes rearing behavior, gait analysis, and the rotarod, to analyze motor deficits in non-exercised and exercised HD mice. The results of the motor behavior tasks suggest significant differences in motor performance for both non-exercised and exercised HD mice in comparison to wild-type. We did not find any significant differences in motor performance between non-exercised and exercised HD mice. These results led us to conclude that intranuclear mHtt protein aggregation is not responsible for the motor deficits found in mice. Future studies will examine the role of mitochondrial stress in progression of HD and motor behavior performance.