Misfolding and aggregation of the protein ?-synuclein (? -syn) is associated with Parkinson's Disease (PD), which is a devastating neurodegenerative movement disorder. In PD, ? -syn misfolds into an aberrant protein conformation, termed amyloid, which is highly stable, possesses a characteristic cross-?? structure, and is largely viewed to be an intractable condition. There is evidence that pre- amyloid oligomers of ? -syn possess greater toxicity than the fibers themselves. Furthermore, certain rare mutations of ? -syn are associated with familial forms of PD and often result in a decreased age of onset and increased severity of symptoms. These mutants have been shown to increase propensity of ? -syn aggregation or to increase the concentration of the pre-amyloid oligomers. A remarkable yeast protein, Hsp104, has been shown to ameliorate symptoms of ? -syn aggregation in a rat model of PD by disaggregating the ? -syn fibers and oligomers. However, high concentrations of Hsp104 were required to observe disaggregation, which reduces the effectiveness of this potential PD therapeutic. Additionally, it is not clear how Hsp104 is able to remodel ? -syn fibers and oligomers, which obscures ways in which this protein may be further developed to treat PD. We have isolated an Hsp104 mutant with even greater potency towards ? -syn fibers, which gives us confidence that Hsp104 will be eventually become a viable PD treatment. The goal of this proposal is to optimize Hsp104 for even higher anti-?? -syn fiber and oligomer activity. We plan on targeting both wild-type and disease associated mutants of ? -syn to ensure that Hsp104 can be used to treat all cases of PD. We also aim to understand the mechanism of Hsp104 disaggregation of ? -syn fibers and oligomers in order to facilitate even further optimization of Hsp104 as a PD therapeutic.
Parkinson's Disease is a devastating neurodegenerative disorder which is characterized by protein misfolding and aggregation in brain tissue. These misfolded proteins, termed amyloid, are very stable and difficult to clear. However, the yeast protein, Hsp104 is able to reverse protein misfolding and clear the amyloid aggregates. We are focusing on two things: First, we will optimize Hsp104 activity so it is more potent against the amyloid aggregates found in Parkinson's patients;and second, we will determine how Hsp104 functions.
|Sweeny, Elizabeth A; Jackrel, Meredith E; Go, Michelle S et al. (2015) The Hsp104 N-terminal domain enables disaggregase plasticity and potentiation. Mol Cell 57:836-49|
|Jackrel, Meredith E; DeSantis, Morgan E; Martinez, Bryan A et al. (2014) Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156:170-82|
|Desantis, Morgan E; Sweeny, Elizabeth A; Snead, David et al. (2014) Conserved distal loop residues in the Hsp104 and ClpB middle domain contact nucleotide-binding domain 2 and enable Hsp70-dependent protein disaggregation. J Biol Chem 289:848-67|
|DeSantis, Morgan E; Leung, Eunice H; Sweeny, Elizabeth A et al. (2012) Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients. Cell 151:778-93|
|DeSantis, Morgan E; Shorter, James (2012) Hsp104 drives ""protein-only"" positive selection of Sup35 prion strains encoding strong [PSI(+)]. Chem Biol 19:1400-10|