ANALYSIS OF ZDHHC17 INTERACTION NETWORKS AND PROTEIN INTERACTIONS LINKED TO NEURODEGENERATION

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The cells in our body contain a diverse array of different proteins that coordinate and drive specific pathways, such as neuronal communication in the brain. These proteins are often tightly regulated to ensure that they perform their specific functions in the required spatial and temporal manner. A major way of regulating protein function is by specific chemical modifications that are made to the amino acid backbone, and a variety of different chemical groups are added to proteins that affect their activity. One important but poorly understood modification is "S-acylation", the attachment of fatty acids onto proteins. S-acylation of cellular proteins is catalysed by a family of twenty-four "zDHHC" enzymes. The importance of these enzymes for normal brain function is underscored by reported links between zDHHC enzyme dysfunction and conditions such as neurodegeneration, schizophrenia, and intellectual disability.Despite the importance of zDHHC enzymes, we lack fundamental knowledge about this protein family, including the substrate interaction networks of individual enzyme isoforms, how changes in these interactions contribute to disease pathology, and how these interactions can be targeted as a therapeutic strategy. Recent work from our group has provided an important breakthrough in this area by identifying a specific protein sequence that is recognised by the enzyme zDHHC17; this enzyme is essential for brain function and is associated with specific neurodegenerative disorders. In this project, we will exploit our new findings about the zDHHC17 recognition sequence to identify the substrate interaction network of this enzyme in neurons, providing a major advance in our understanding of the physiological functions of zDHHC17. In addition, we will investigate how the interaction of zDHHC17 with one of its key substrates, huntingtin, is affected in Huntington's disease to provide new insight into the pathogenesis of this neurodegenerative disorder. Finally, we will employ the novel information on the zDHHC17 recognition sequence to develop compounds that may have potential for the treatment of the neurodegenerative disease, neuronal ceroid lipofuscinosis. Collectively, these studies focused on the zDHHC17 recognition sequence will provide new information on the physiological functions of zDHHC17, its links with Huntington's disease, and the potential of this enzyme to serve as a novel therapeutic target for neuronal ceroid lipofuscinosis.