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HD InsightsGreasing the Huntington Disease Brain: Palmitoylation as a therapeutic target

By: Shaun S. Sanders, PhD

Much of our current understanding of the functions of wildtype HTT and of the pathological processes of mHTT comes from studies involving its interacting partners. Many studies seek to determine the full spectrum of HTT interacting proteins (HIPs) and to understand how their interactions are altered by mHTT, since interactions altered by mHTT may contribute to HD.1-3 In particular, HIP14 (DHHC17) and HIP14L’s (HIP14-like or DHHC13) interactions with HTT are inversely related to polyglutamine tract length.4,5 These findings prompted further investigation into the role that these two proteins play in HD.

image cHIP14 and HIP14L belong to a family of enzymes called DHHCdomain-containing palmitoyl acyltransferases (PATs).6,7 PATs mediate palmitoylation, the reversible, post-translational addition of the 16-carbon fatty acid palmitate to cysteine residues on proteins.8,9 HTT is palmitoylated by HIP14 and HIP14L7,10 on cysteine 214 (see Figure), but interestingly, mHTT is less palmitoylated.11 Humans have 23 PATs. HIP14 and HIP14L are the only two that have N-terminal ankyrin repeat domains6 that mediate the interaction with HTT.10 HTT undergoes many different types of post-translational modifications, many of which are altered in the presence of mHTT. This is believed to contribute to mHTT toxicity and cell death.12 Indeed, loss of palmitoylation of mHTT increases its toxicity and aggregation.11 Therefore, increasing palmitoylation is a potential therapeutic strategy for HD treatment.

Further validation of this modification as an HD therapeutic target comes from the striking HD-like phenotypes of the Hip14- and Hip14l-deficient mouse models (Hip14-/- and Hip14l-/-, respectively). Both of these mouse models mimic phenotypes of full-length HD mouse models, in particular the motor deficits and striatal degeneration of the YAC128 mouse. The phenotype of the Hip14-/- mouse model is more severe and of earlier onset than that of the Hip14l-/- mouse model, whose phenotype is adult onset and progressive.5, 13 Surprisingly, HTT palmitoylation is not altered in either of these mouse models. This leads to the hypothesis that altered palmitoylation of other HIP14 and HIP14L substrates, in addition to HTT, increases toxicity in HD.5,13 This is possible because HTT is not only a substrate of HIP14, but in fact modulates HIP14 activity, which is decreased in HD mouse models.10 In addition, HIP14 and HTT share a large number of interactors,14 which suggests that loss of HIP14 activity in HD mice leads to the underpalmitoylation of multiple HIP14 substrates.13

There is mounting evidence that aberrant palmitoylation plays a role in HD. However, it is difficult to target HIP14 or HIP14L to increase their activity and thereby increase palmitoylation of HTT and other substrates. A second group of enzymes, acyl protein thioesterases (APTs), mediate depalmitoylation and may be more suitable targets to increase palmitoylation in HD. There are four known APTs: the cytoplasmic APT1, APT2, and APTL1, and the lysosomal PPT1, which mediates depalmitoylation prior to protein degradation.15, 16 It is currently unknown which APT depalmitoylates HTT and other HIP14/HIP14L substrates. Currently available small molecule inhibitors of APTs should be assessed for efficacy in improving HD phenotypes in HD models to further validate palmitoylation as a therapeutic target in HD. Future goals for therapeutic development would be to improve current small molecule drugs or to develop new drugs to target APTs in HD.

1Shirasaki DI, Greiner ER, Al-Ramahi I, et al. Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron. 2012 Jul 12; 75(1):41-57.

2Culver BP, Savas JN, Park SK, et al. Proteomic analysis of wildtype and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement i n protein synthesis. J Biol Chem. 2012 Jun 22; 287(26):21599-614.

3Schaefer MH, Fontaine JF, Vinayagam A, et al. HIPPIE: Integrating protein interaction networks with experiment based quality scores. PLoS One. 2012; 7(2):e31826.

4Singaraja RR, Hadano S, Metzler M, et al. HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet. 2002 Nov 1; 11(23):2815-28.

5Sutton LM, Sanders SS, Butland SL, et al. Hip14l-deficient mice develop neuropathological and behavioural features of Huntington disease. Hum Mol Genet. 2013 Feb 1; 22(3):452-65.

6Ohno Y, Kihara A, Sano T, Igarashi Y. Intracellular localization and tissue-specific distribution of human and yeast DHHC cysteine-rich domain-containing proteins. Biochim Biophys Acta. 2006 Apr; 1761(4):474-83.

7Huang K, Yanai A, Kang R, et al. Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron. 2004 Dec 16;44(6):977-86.

8Hallak H, Muszbek L, Laposata M, et al. Covalent binding of arachidonate to G protein alpha subunits of human platelets. J Biol Chem. 1994 Feb 18; 269(7):4713-6.

9Smotrys JE, Linder ME. Palmitoylation of intracellular signaling proteins: regulation and function. Annu Rev Biochem. 2004; 73:559-87.

10Huang K, Sanders SS, Kang R, et al. Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14. Hum Mol Genet. 2011 Sep 1; 20(17):3356-65.

11Yanai A, Huang K, Kang R, et al. Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci. 2006 Jun; 9(6):824-31.

12Ehrnhoefer DE, Sutton L, Hayden MR. Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist. 2011 Oct;17(5): 475-92.

13Singaraja RR, Huang K, Sanders SS, et al. Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Hum Mol Genet. 2011 Oct 15;20(20):3899-909.

14Butland SL, Sanders SS, Schmidt ME, et al. The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington’s disease. Hum Mol Genet. 2014 Aug 1; 23(15): 4142-60.

15Young FB, Butland SL, Sanders SS, et al. Putting proteins in their place: palmitoylation in Huntington disease and other neuropsychiatric diseases. Prog Neurobiol. 2012 May;97(2): 220-38.

16Tian L, McClafferty H, Knaus HG, et al. Distinct acyl protein transferases and thioesterases control surface expression of calcium-activated potassium channels. J Biol Chem. 2012 Apr 27; 287(18):14718-25.

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