Study Rationale:
Parkinson’s disease (PD) is driven by many factors, but a common feature is the buildup of a sticky protein called alpha-synuclein. These protein clumps can damage the lysosome, the “recycling center” of the cell, which is already known to malfunction in many genetic forms of PD. Damaged lysosomes fail to break down waste properly, making nerve cells more vulnerable. By combining powerful imaging (cryo-electron tomography, or cryo-ET) with chemical analysis of fats (lipidomics), this project will uncover how alpha-synuclein damages lysosomes and how genetic risk factors make the problem worse.
Hypothesis:
We propose that alpha-synuclein clumping and lysosome failure form a harmful feedback loop in PD. If lysosomes are weak, alpha-synuclein spreads more easily, and if alpha-synuclein spreads, lysosomes are further damaged. Strengthening lysosomes may break this cycle and protect nerve cells.
Study Design:
We will use cryo-ET, an advanced form of electron microscopy, to view how alpha-synuclein damages lysosomes inside nerve cells at the molecular level. We will also measure changes in lysosomal lipids that cannot be seen with imaging, using specialized lipidomics approaches. Together, these methods will link structure to chemistry in damaged lysosomes. We will test nerve cells carrying PD-linked gene changes (such as LRRK2, GBA1, and VPS13C) and compare them to healthy cells. Finally, we will explore whether boosting lysosome repair or biogenesis can reverse the damage and restore normal function.
Impact on Diagnosis/Treatment of Parkinson’s disease:
This study could reveal new weak points in lysosomes that drive PD progression and reveal new therapeutic targets. If successful, the results will guide therapies that strengthen lysosomes, making them more resistant to alpha-synuclein damage. Such strategies could slow or prevent disease progression in both genetic and sporadic PD.
Next Steps for Development:
If our approach works, the next step is to test drugs or genetic tools that restore healthy lysosome structure and lipid composition in cell models of PD. These efforts will set the stage for early-stage therapeutic development aimed at breaking the harmful cycle between lysosome failure and alpha-synuclein spread.