H D I N S I G H T S
HD Insights, Vol. 11 6
1
Renna M, Jimenez-Sanchez M, Sarkar S, Rubinsztein DC.
Chemical inducers of autophagy that enhance the clearance of
mutant proteins in neurodegenerative diseases J Biol Chem. 2010
Apr 9;285(15):11061-7.
2
Wong E, Cuervo AM. Autophagy gone awry in
neurodegenerative diseases. Nat Neurosci. 2010 Jul;13(7):805-11.
3
Martin DD, Heit RJ, Yap MC, et al. Identification of a post-
translationally myristoylated autophagy-inducing domain
released by caspase cleavage of huntingtin. Hum Mol Genet.
2014 Jun 15;23(12):3166-79.
4
Graham RK, Deng Y, Carroll J, et al. Cleavage at the 586 amino
acid caspase-6 site in mutant huntingtin influences caspase-6
activation in vivo. J Neurosci. 2010 Nov 10;30(45):15019-29.
5
Graham RK, Deng Y, Slow EJ, et al. Cleavage at the
caspase-6 site is required for neuronal dysfunction and
degeneration due to mutant huntingtin. Cell. 2006 Jun 16;125(6):
1179-91.
6
Martin DD, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy
in Huntington disease and huntingtin in autophagy. Trends
Neurosci. 2015 Jan;38(1):26-35.
7
Ochaba J, Lukacsovich T, Csikos G, et al. Potential function for
the Huntingtin protein as a scaffold for selective autophagy. Proc
Natl Acad Sci USA. 2014 Nov 25;111(47):16889-94.
8
Rui YN, Xu Z, Patel B, et al. Huntingtin functions as a scaffold
for selective macroautophagy. Nat Cell Biol. 2015 Mar;17(3):
262-75.
Copyright © Huntington Study Group 2015. All rights reserved.
By: Dagmar Ehrnhoefer, PhD
Unraveling the Cause of Dysfunctional
Autophagy in HD
H D I N S I G H T S
Mutant huntingtin (mHTT) is the direct cause of HD, and many exciting new treatment strategies are aimed at lowering its levels.
The primary approach is to prevent generation of mHTT. However, there are also intracellular mechanisms to clear mHTT once it
has been generated, and even mHTT aggregates can be degraded. The mechanism for this is autophagy, meaning "self-eating."
Autophagy requires cargo proteins to be tagged with an autophagy adaptor protein such as p62, which then links the tagged
protein to a membrane structure that slowly closes in around both adaptor and cargo. This autophagic membrane vesicle, called
an autophagosome, then undergoes a series of degradation steps to finally clear the cell of unwanted dysfunctional or mutant
proteins.
It has been known for some time that autophagy is impaired in HD, and that this impairment contributes to the accumulation of
mHTT and its aggregates. In fact, the chemical up-regulation of autophagy has shown beneficial effects in mouse and Drosophila
models of HD.
1
However, there is substantial evidence to suggest that in HD, cargo proteins are not efficiently loaded into
autophagosomes
2
, a defect that must
first be corrected before mHTT
degradation can take place efficiently.
More details about this dysfunction
have come to light in the past year, as
multiple studies have shown that
wild-type HTT plays an important
role in autophagy (Figure). This role
is mediated through post-
translational modifications: a
fragment of HTT released by caspase
cleavage at aa552 can undergo
myristoylation at aa553, a lipid
modification that anchors HTT to the
ER membrane
3
, where it facilitates the
formation of autophagosomes.
Myristoylation is significantly
reduced in the presence of mHTT,
suggesting that the normal function of HTT is disrupted. Interestingly, caspase cleavage of HTT is itself a process that is tightly
linked to HTT toxicity
4
and, in particular, cleavage at aa586 is important for pathogenesis to occur in a mouse model of HD.
5
We
have therefore recently suggested that preventing mHTT cleavage at aa586 may shift proteolysis to favor processing at aa552,
which would lead to increased myristoylation and autophagy, and promote the clearance of misfolded mHTT.
6
In addition, two independent studies have shown that HTT can act as a scaffold in autophagy initiation, bringing together the
autophagy adaptor protein p62 and ULK1, a kinase that initiates autophagy.
7,8
The regions of the HTT protein that are required for
binding p62 and ULK1 are at the C-terminus, distal from the aa586 caspase cleavage site. All data taken together suggest that
cleavage of HTT at aa586 separates the myristoylated 'membrane-anchor' (aa553) from other, more C-terminal domains crucial for
the interaction of HTT with other autophagy proteins.
6
Since mHTT is both cargo and part of the autophagic machinery, a more
detailed investigation of these pathways and how they are disrupted in the presence of mHTT could identify therapeutic targets
to increase the autophagic clearance of mHTT, a promising approach to lowering overall levels of mHTT.
Figure. Huntingtin is an autophagy protein as well as autophagic cargo.
Graphics courtesy of Erin Kenzie and Dale D.O. Martin.
