Low Levels of Human HIP14 Are Sufficient to Rescue Neuropathological, Behavioural, and Enzymatic Defects Due to Loss of Murine HIP14 in Hip14−/− Mice

Fiona B Young,Shaun Sanders,Natalie C M Tam,Nagat Bissada,Michael R Hayden,Chris Kay,Roshni R Singaraja,Weining Zhang,Kun Huang,Yu Deng,Sonia Franciosi,Amanda Spreeuw

doi:10.1371/journal.pone.0036315

Fiona B Young, Shaun Sanders + Show 10 more

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https://doi.org/10.1371/journal.pone.0036315

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Abstract

Huntingtin Interacting Protein 14 (HIP14) is a palmitoyl acyl transferase (PAT) that was first identified due to altered interaction with mutant huntingtin, the protein responsible for Huntington Disease (HD). HIP14 palmitoylates a specific set of neuronal substrates critical at the synapse, and downregulation of HIP14 by siRNA in vitro results in increased cell death in neurons. We previously reported that mice lacking murine Hip14 (Hip14−/−) share features of HD. In the current study, we have generated human HIP14 BAC transgenic mice and crossed them to the Hip14−/− model in order to confirm that the defects seen in Hip14−/− mice are in fact due to loss of Hip14. In addition, we sought to determine whether human HIP14 can provide functional compensation for loss of murine Hip14. We demonstrate that despite a relative low level of expression, as assessed via Western blot, BAC-derived human HIP14 compensates for deficits in neuropathology, behavior, and PAT enzyme function seen in the Hip14−/− model. Our findings yield important insights into HIP14 function in vivo.

Highlights

Protein palmitoylation involves the reversible addition of palmitic acid to cysteine residues via a thioester bond, and plays a key role in protein trafficking and neuronal function [1,2]
Far less is known about the acyl protein thioesterases that are thought to catalyze palmitate removal [13], but their importance in regulation of protein palmitoylation has been highlighted by patients with mutations in the thioesterase PPT1 (Entrez Gene ID 5538) that result in neuronal ceroid lipofuscinosis [14]
In this study we have demonstrated that human Huntingtin Interacting Protein 14 (HIP14) can compensate for the Hip142/2 phenotype in functional measures of neuropathology, behavior, and palmitoyl acyl transferase (PAT) enzyme function

Summary

Introduction

Protein palmitoylation involves the reversible addition of palmitic acid to cysteine residues via a thioester bond, and plays a key role in protein trafficking and neuronal function [1,2]. PAT dysfunction or loss has been associated with several human diseases, including mental retardation (OMIM *300646, *300576) [7,8], schizophrenia (OMIM *608784) [9,10,11], and Alzheimer’s Disease (#104300) [12]. Far less is known about the acyl protein thioesterases that are thought to catalyze palmitate removal [13], but their importance in regulation of protein palmitoylation has been highlighted by patients with mutations in the thioesterase PPT1 (Entrez Gene ID 5538) that result in neuronal ceroid lipofuscinosis [14]. HD results from an expansion of the CAG repeat in the HD gene, resulting in a polyglutamine (poly-Q)

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