Low levels of human HIP14 are sufficient to rescue neuropathological, behavioural, and enzymatic defects due to loss of murine HIP14 in Hip14-/- mice.
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.
Department of Medical Genetics and Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Fiona B
FB
Young
Sonia
S
Franciosi
Amanda
A
Spreeuw
Yu
Y
Deng
Shaun
S
Sanders
Natalie C M
NC
Tam
Kun
K
Huang
Roshni R
RR
Singaraja
Weining
W
Zhang
Nagat
N
Bissada
Chris
C
Kay
Michael R
MR
Hayden
D000217:Acyltransferases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D054878:Lipoylation; D008124:Locomotion / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D060888:Real-Time Polymerase Chain Reaction; D045442:Rotarod Performance Test
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D000217:Acyltransferases; C473038:ZDHHC17 protein, human; C569387:Zdhhc17 protein, mouse