Study Rationale:
Parkinson’s disease is a disorder of protein misfolding and aggregation. It is characterized by the presence of Lewy bodies and Lewy neurites: aberrant intracellular structures containing misfolded and aggregated alpha-synuclein that accumulate in cells of the central nervous system. In healthy cells, protein misfolding and aggregation is prevented or reversed by various protein quality control (PQC) systems. However, we lack a complete understanding of these systems, which hinders our ability to develop therapies for PD and other neurodegenerative diseases. Our laboratory has recently discovered a PQC system in humans that is highly effective in suppressing alpha-synuclein aggregation.
Hypothesis:
We hypothesize that boosting the activity of this PQC system in neuronal cells will be beneficial for the treatment of PD.
Study Design:
We will characterize the various proteins that comprise this novel PQC system in test tubes and identify the one that displays the greatest ability to dismantle or prevent the formation of alpha-synuclein aggregates. We will then assess how this PQC protein performs in in preclinical PD models using a gene therapy approach to introduce it into brain cells.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Because alpha-synuclein accumulation is a hallmark of PD, these experiments will potentially identify novel therapeutics that can be used for the treatment of all PD subtypes, regardless of the condition’s origin or cause.
Next Steps for Development:
If successful, we will plan to perform toxicology tests in additional preclinical models and conduct other studies leading to an investigational new drug (IND) application.