Dr. Scoty Hearst
A functional analysis of matrix metalloproteinases as therapeutic targets in neurodegenerative diseases using a Drosophila model of Spinocerebellar Ataxia Type 1
Matrix metalloproteases (MMPs) are present in many cells of the central nervous system (CNS). MMPs are calcium (Ca2+) dependent zinc (Zn2+) containing endopeptidases that once activated participate in the regulation of diverse physiological and pathological processes. Several of the MMP family members play important roles in the development, injury, and repair of neurological diseases. Recently MMPs have gained much attention as therapeutic targets in neurodegenerative disorders due to up-regulation of MMPs observed in a variety of CNS disorders, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), polyglutamine diseases like Huntington’s disease (HD) and Spinocerebellar Ataxia Type 1 and 3 (SCA1 and 3), and in neuroinflammatory conditions such as traumatic brain injury, meningitis, and stroke. MMPs are strictly regulated endopeptidases and in humans 28 different MMPs are regulated by four different types of tissue inhibitors of metalloproteinases (TIMPs). MMPs can be a double-edged sword, due to their essential function in neurorepair and their destructive function in neurodegeneration. The exact mechanisms of MMPs in neurodegeneration are poorly understood and further complicated by the large number of MMPs and TIMPs expressed by humans and other vertebrates. We propose to leverage both in vitro and in vivo techniques to gain a functional understanding of the role of MMPs in neurodegenerative diseases and as a therapeutic target. In vitro studies will focus on elucidating the functional role of MMPs in neurophysiological development using neuronal cell cultures. In vivo studies will utilize the fruit fly Drosophila melanogaster as a model system since it has only two MMP genes, dmmp-1 and dmmp-2, and may hold the key to a better understanding of the distinct roles of MMPs in neurodegeneration. Our central hypothesis is that MMP-1 and MMP-2 will be a therapeutic target in the progression of neurodegenerative diseases. We propose to test our hypothesis with two specific aims: (a) Characterize the precise role of MMP1 and MMP2 in cell differentiation, neurite formation and toxin protein metabolism using neuronal cell cultures and (b) Explore the MMPs as therapeutic targets in SCA1 disease progression using selective MMP inhibitors and MMP modulators in a Drosophila SCA1 model. The long-term goal of this project is to reveal the distinctive roles of MMPs in neurodegenerative diseases such as SCA1 and to further develop selective MMP inhibitors or modulators as possible therapeutics for neurodegenerative disorders.