Spinocerebellar ataxia type 3 (SCA3), also known as
Machado-Joseph Disease, is a progressive
neurodegenerative disorder characterized by loss of neuronal matter due to the expansion of the CAG repeat in the ATXN3/MJD1 gene and subsequent
ataxin-3 protein. Although the underlying pathogenic
protein expansion has been known for more than 20 years, the complexity of its effects is still under exploration. The
ataxin-3 protein in its expanded form is known to aggregate and disrupt cellular processes in neuronal tissue but the role of the
protein on populations of immune cells is unknown. Recently, mast cells have emerged as potential key players in
neuroinflammation and neurodegeneration. Here, we examined the mast cell-related effects of
ataxin-3 expansion in the brain tissues of 304Q
ataxin-3 knock-in mice and SCA3 patients. We also established cultures of mast cells from the 304Q knock-in mice and examined the effects of 304Q
ataxin-3 knock-in on the immune responses of these cells and on markers involved in mast cell growth, development and function. Specifically, our results point to a role for expanded
ataxin-3 in suppression of mast cell marker CD117/c-Kit, pro-inflammatory
cytokine TNF-α and NF-κB inhibitor IκBα along with an increased expression of the granulocyte-attracting
chemokine CXCL1. These results are the beginning of a more holistic understanding of
ataxin-3 and could point to the development of novel therapeutic targets which act on
inflammation to mitigate symptoms of SCA3.