Our Research
Established in 2014 at the University of Minnesota, the Cvetanovic Lab seeks to understand how the interactions of neurons, astrocytes, and microglia influence the onset and progression of neurodegenerative diseases. In particular we study the pathogenesis of the inherited neurodegenerative disease Spinocerebellar ataxia type 1(SCA1). SCA1 belongs to a broader family of polyglutamine diseases, including Huntington’s disease and other SCA's. Polyglutamine diseases are caused by the expansion of CAG repeat (encoding for glutamine) in the coding region of Ataxin-1 gene. We seek to further understand the effects of expanded Ataxin-1 using primary culture, mouse genetics, cell and molecular biology techniques, mouse behavior, confocal microscopy, flow cytometry, and induced pluripotent stem cells.
The ultimate goal of our laboratory is to increase knowledge of the cellular and molecular pathways that underlie the pathology of neurodegenerative disorders, thereby opening new avenues for therapeutic approaches. A key focus of the lab is to train the next generations of scientists by creating a supportive environment that is conductive to learning, creating and testing new ideas.
The Duality of Astrocytes in SCA1:
We propose that astroglia actively contribute to the pathogenesis of SCA1 in a bi-modal, disease stage dependent manner. We propose that during early pre-symptomatic stage, astroglial are in most part neuroprotective and can compensate for the early dysfunction of PNs, helping maintain a functional cerebellar network. With disease progression astroglial role changes to neurotoxic contributing to the manifestations of PN’s dysfunction and motor deficits. We are investigating signaling pathways that control astroglial phenotypes throughout disease progression.
Brain Derived Neurotrophic Factor
While mutant ATXN1 is expressed from an early age, disease onset usually occurs in patient's mid-thirties, indicating the presence of compensatory factors that limit the toxic effects of mutant ATXN1 early in disease. Brain derived neurotrophic factor (BDNF) is a growth factor known to be important for the survival and function of cerebellar neurons. Using gene expression analysis, we observed altered BDNF expression in the cerebella of mouse models of SCA1, with increased expression during the early stage and decreased expression in the late stage of disease. We are investigating the potentially protective role of BDNF in early and late stages of SCA1 through intraventricular delivery of BDNF via ALZET osmotic pumps on motor and cognitive deficits, brain pathology and gene expression changes in different mouse models of SCA1.
The Cerebellum:
Another focus of the lab is examining changes in intra- and inter-cerebellar connectivity and cerebellar function in SCA1.
Translational approaches to the study of SCA1:
Mouse models of SCA1 were instrumental in understanding the cellular and molecular mechanisms by which mutant ATXN1 causes neurodegeneration. We are currently examining how mutant ATXN1 affects human neurons and glia created from induced pluripotent stem cells (iPSCs) derived from patients with SCA1 in order to translate this knowledge gained from mouse models.