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HD InsightsUnraveling the Cause of Dysfunctional Autophagy in HD

By: Dagmar Ehrnhoefer, PhD

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.

figureIt 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 autophagosomes2, 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 membrane3, 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 toxicity4 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.

1Renna 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.

2Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci. 2010 Jul;13(7):805-11.

3Martin DD, Heit RJ, Yap MC, et al. Identification of a posttranslationally myristoylated autophagy-inducing domain released by caspase cleavage of huntingtin. Hum Mol Genet. 2014 Jun 15;23(12):3166-79.

4Graham 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.

5Graham 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.

6Martin DD, Ladha S, Ehrnhoefer DE, Hayden MR. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 2015 Jan;38(1):26-35.

7Ochaba 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. 8Rui YN, Xu Z, Patel B, et al. Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015 Mar; 17(3): 262-75

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