Over the last decade, studies have revealed that diminishing mutant huntingtin levels in mouse models of Huntington's disease (HD) leads to the amelioration of pre-existing symptoms, raising the tantalizing possibility for a cure. One of the primary events that accompany symptomatic reversal is the concomitant clearance of the aggregated mutant protein. Despite the intense debate that surrounds the role of protein aggregation in the pathogenesis of HD, a great amount of effort has been put forward to inhibit or disaggregate these proteinaceous intracellular deposits, with limited success. More recently, efforts to drive the turnover of these structures have been proposed, with some promise. One difficulty with these studies has been the inability to target protein degradation pathways in such a way to either enhance or impede the selective elimination of the aggregates, often leading to unwanted, nonspecific consequences that obscure the interpretation of the studies outcome. Recent studies have emerged demonstrating that the protein degradation pathway macroautophagy is capable of the selective degradation of various cargo including ubiquitinated protein aggregates. We have identified the Autophagy linked FYVE domain protein (Alfy) as essential to this process: Importantly not only does depletion of Alfy inhibit the macroautophagic clearance of aggregated mutant htt, but it does so without inhibiting basal and starvation-mediated macroautophagy. Moreover, over-expression of Alfy in neurons led to fewer mutant huntingtin inclusions. In response to the PAS-10-183 Validation of Novel Therapeutic Targets for Huntington's disease, we propose to use Alfy to genetically determine whether the clearance of aggregated mutant huntingtin represents a valid therapeutic approach in HD.
Huntington's disease is a devastating, inherited neurodegenerative disorder that affects 5 to 10 persons per every 100,000. By understanding the cellular events that affect the disease may not only help cure HD, but may also shed insight into sporadic disorders such as Parkinson's disease, Alzheimer's disease and Lou Gehrig's disease. Our goal is to determine if the elimination of protein aggregates, a common feature across most adult onset neurodegenerative diseases, represents a viable therapeutic strategy.
|Eenjes, Evelien; Dragich, Joanna M; Kampinga, Harm H et al. (2016) Distinguishing aggregate formation and aggregate clearance using cell-based assays. J Cell Sci 129:1260-70|
|Dragich, Joanna M; Kuwajima, Takaaki; Hirose-Ikeda, Megumi et al. (2016) Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain. Elife 5:|
|Yang, X William; Yamamoto, Ai (2014) CLEARance wars: PolyQ strikes back. Nat Neurosci 17:1140-2|
|Prè, Deborah; Nestor, Michael W; Sproul, Andrew A et al. (2014) A time course analysis of the electrophysiological properties of neurons differentiated from human induced pluripotent stem cells (iPSCs). PLoS One 9:e103418|
|Nath, Sangeeta; Dancourt, Julia; Shteyn, Vladimir et al. (2014) Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nat Cell Biol 16:415-24|
|Tang, Guomei; Gudsnuk, Kathryn; Kuo, Sheng-Han et al. (2014) Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83:1131-43|
|Yamamoto, Ai; Yue, Zhenyu (2014) Autophagy and its normal and pathogenic states in the brain. Annu Rev Neurosci 37:55-78|
|Shoji-Kawata, Sanae; Sumpter, Rhea; Leveno, Matthew et al. (2013) Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494:201-6|
|Johnson, Christopher W; Melia, Thomas J; Yamamoto, Ai (2012) Modulating macroautophagy: a neuronal perspective. Future Med Chem 4:1715-31|
|Mijaljica, Dalibor; Nazarko, Taras Y; Brumell, John H et al. (2012) Receptor protein complexes are in control of autophagy. Autophagy 8:1701-5|