Jared Cullen, B.S.
Doctoral Student
Connor Lab
Department of Communication Sciences and Disorders
Department of Otolaryngology–Head and Neck Surgery
University of Wisconsin-Madison
Oromotor Dysfunction in a Rat Model of Alexander Disease
Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by dominant gain of function mutations in the glial fibrillary acidic protein (GFAP) gene, leading to protein aggregation, astrocyte dysfunction, white matter degeneration, and progressive neurological decline. Individuals with AxD frequently experience bulbar impairments, including dysphagia, feeding difficulties, compromised airway protection, and dysarthria, however these deficits have not yet been characterized in preclinical animal models.
Our research assessed oromotor function in the CRISPR/Cas9-engineered GFAP+/R237H rat model, which carries the rodent equivalent of the severe and clinically prevalent human R239H mutation. To determine whether this model recapitulates clinically observed bulbar motor deficits, we conducted a series of baseline behavioral assays including tongue strength, mastication efficiency, swallowing function, and ultrasonic vocalizations to measure function directly related to swallowing and speech.
Findings from this work establish the first evidence of oromotor dysfunction in an AxD animal model, paralleling bulbar motor impairments observed clinically in individuals with AxD. These results strengthen the translational relevance of the GFAP+/R237H rat model and its validity as a robust tool for future mechanistic studies and the development of therapeutic and/or rehabilitative techniques aimed at improving the bulbar function in Alexander disease.
This work was funded by NIH grants: P01HD076892, R01DC008149, T32DC009401, R01DC018071, R01AG085564, R37CA225608, and R01NS117469.