Funded Studies
Study Rationale: The protein alpha-synuclein forms harmful clusters or aggregates that can kill neurons in the brains of people with Parkinson’s disease (PD). Neurons attempt to eliminate these clumps by sequestering them in lysosomes, structures whose acidic interior can break down the aggregates. To track the fate of alpha-synuclein in neurons, researchers use imaging tools (‘reporters’) consisting of the alpha-synuclein protein linked to a fluorescent marker that can be viewed with a microscope. A major problem with the current set of alpha-synuclein reporters is that their fluorescent markers do not produce a signal in the low pH environment of lysosomes.
Hypothesis: We hypothesize that an alpha-synuclein reporter with a fluorescent marker that produces a signal in a low-pH environment can be used to track the fate of aggregates in acidic cellular structures such as lysosomes by microscopy.
Study Design: We will develop a new reporter consisting of alpha-synuclein linked to a marker protein that fluoresces under acidic conditions. This alpha-synuclein reporter will be tested for its ability to emit a strong fluorescent signal and to form aggregates similar to the native alpha-synuclein protein (without an attached marker)—both as a purified protein in a test tube and when produced in cultured neurons.
Impact on Diagnosis/Treatment of Parkinson’s disease: The alpha-synuclein reporter developed here will enable researchers to better understand how protein aggregates are broken down in acidic lysosomes and why this process fails in PD. The reporter will also serve as a powerful tool to discover drugs that eliminate alpha-synuclein aggregates in the brains of people with PD.
Next Steps for Development: The next steps toward clinical application of our findings will be to use this reporter to track the fate of alpha-synuclein aggregates in preclinical models of PD and to screen for drugs that enhance the breakdown of alpha-synuclein aggregates in lysosomes.