Reversing deleterious protein aggregation with re-engineered protein disaggregases

Abstract

Aberrant protein folding is severely problematic and manifests in numerous disorders, including amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), Huntington disease (HD), and Alzheimer disease (AD). Patients with each of these disorders are characterized by the accumulation of mislocalized protein deposits. Treatments for these disorders remain palliative, and no available therapeutics eliminate the underlying toxic conformers. An intriguing approach to reverse deleterious protein misfolding is to upregulate chaperones to restore proteostasis. We recently reported our work to re-engineer a prion disaggregase from yeast, Hsp104, to reverse protein misfolding implicated in human disease. These potentiated Hsp104 variants suppress TDP-43, FUS, and α-synuclein toxicity in yeast, eliminate aggregates, reverse cellular mislocalization, and suppress dopaminergic neurodegeneration in an animal model of PD. Here, we discuss this work and its context, as well as approaches for further developing potentiated Hsp104 variants for application in reversing protein-misfolding disorders.

Keywords: :

• Hsp104
• protein-misfolding disorders
• proteostasis
• amyloid
• disaggregation
• neurodegeneration

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

Our studies were supported by: an American Heart Association Post-Doctoral Fellowship (M.E.J); NIH Director’s New Innovator Award DP2OD002177, NIH grants R21NS067354, R21HD074510, and R01GM099836, a Muscular Dystrophy Association Research Award (MDA277268), Packard Center for ALS Research at Johns Hopkins University, Target ALS, and an Ellison Medical Foundation New Scholar in Aging Award (J.S.).