H D I N S I G H T S
HD Insights, Vol. 11 7
Copyright © Huntington Study Group 2015. All rights reserved.
By: Shaun S. Sanders, PhD
Greasing the Huntington Disease Brain
Palmitoylation as a therapeutic target
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.
HIP14 and HIP14L belong to a family of enzymes called DHHC-
domain-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
HIP14L
7,10
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
domains
6
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.
H D I N S I G H T S
Figure. Wild-type HTT is palmitoylated by HIP14/
HIP14L, while depalmitoylation depends on acyl
protein thioesterases (APTs).
1
Shirasaki 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.
2
Culver BP, Savas JN, Park SK, et al. Proteomic analysis of wild-
type 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.
3
Schaefer MH, Fontaine JF, Vinayagam A, et al. HIPPIE:
Integrating protein interaction networks with experiment based
quality scores. PLoS One. 2012;7(2):e31826.
4
Singaraja 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.
5
Sutton 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.
6
Ohno 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.
7
Huang 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.
8
Hallak 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.
9
Smotrys JE, Linder ME. Palmitoylation of intracellular signaling
proteins: regulation and function. Annu Rev
Biochem. 2004;73:559-87.
10
Huang 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.
11
Yanai 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.
12
Ehrnhoefer 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.
13
Singaraja 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.
14
Butland 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.
15
Young 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.
16
Tian 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.
