The Role of Matrix Metalloproteinases In The Metabolism Of ATXN1 Protein Aggregates
Desiree Mills1, Kennadi Johnson1, Cendonia Thomas1, Natraj Krishnan2, Scoty Hearst1
1Department of Biology, Tougaloo College, Tougaloo MS
2Department of Biochemistry, Molecular Biology, Entomology and Plant Pathology, Mississippi State University, Mississippi State, MS
Spinocerebellar Ataxia Type 1 (SCA1) is a fatal neurodegenerative disease caused by a mutation in the poly-glutamine stretch of the ATXN1 protein. ATXN1 proteins form nuclear inclusion bodies in vivo and in vitro. It is speculated that accumulation of the mutated ATXN1 causes a gain-of-function resulting in neuronal death in the cerebellum and brainstem of SCA1 patients. Matrix metalloproteinase (MMPs) are zinc-dependent endopeptidases that have gained popularity as possible therapeutic targets in neurodegenerative disease. Recent studies have shown that MMPs can degrade toxic poly-glutamine aggregates in Huntington’s disease contributing to its’ disease pathology. We hypothesize that MMPs will also degrade the toxic poly-glutamine aggregates in the SCA1 diseases. To test our hypothesis, we generated GFP-dMMP constructs and mCherry-ATXN1 constructs to express in SHSH5Y neuroblastoma cell lines. We speculated that co-expression of dMMPs with the ATXN1 constructs will reduce nuclear inclusion body formation. Here, we have transiently expressed our GFP-dMMP and mCherry constructs in neuroblastoma. We found that dMMPs can localize to the nucleus, where they may interact with ATXN1. This is the first time that nuclear localization of MMPs have been demonstrated. This paves the way for future co-expression studies. This work is critical to supporting our long-term goal, which is to test the efficiency of MMP inhibitors as SCA1 therapeutics using the drosophila SCA1 animal model. This work was supported by the Mississippi INBRE, funded by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103476. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of General Medical Sciences or the National Institutes of Health.