Progress Report
Study Rationale:
Energy failure in nerve cells is a hallmark of Parkinson’s disease. Our latest research shows that when sugar level is low, neurons switch to a fat-based backup fuel stored in tiny droplets called lipid droplets (LD). In Parkinson’s disease (PD), pathogenic α-synuclein proteins bind to the fat-droplets leading to their build up in neurons. These sticky proteins also latch onto mitochondria, the powerhouse of cells and compromise their ability to generate energy. We will test whether α-synuclein binding to lipid droplets block the flow of fat-based fuel to mitochondria, lowering neuron’s energy (ATP), and causing nerve endings (synapses) to fail.
Hypothesis:
We hypothesize that in Parkinson’s, the pathogenic form of α-synuclein crowds the surface of neuronal lipid droplets, hindering fat-breaking enzymes to access fats and the droplet’s contact with mitochondria so fatty fuels cannot reach them—starving synapses of energy. We will test if restoring fat flow or safely boosting compensatory energy pathways will revive ATP synthesis and synaptic function of neurons.
Study Design:
We will study dopaminergic neurons (DN), the cells that hit hardest in Parkinson’s disease. First, we will introduce disease-linked forms of α-synuclein to DN and measure mitochondrial health — what extent are they stressed and how well their membrane potential is maintained. Using different sensors, we will read out energy production efficiency of mitochondria and the availability of energy at synapses, then link those readings to synaptic performance. To unveil the mechanism, we will visualize how α-synucleins influence lipid droplets interaction with mitochondria. Furthermore, we will analyze purified mitochondria to see how alpha-synuclein changes their metabolic makeup. Finally, we will design strategies to restore energy by reopening fatty fuel flow to mitochondria or by activating alternate pathways that can boost backup energy production when mitochondria are inefficient.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Mapping this energy bottleneck will guide future biomarkers and targeted therapies aimed at protecting brain’s failing energy circuits in Parkinson’s disease. More specifically, by pinpointing where exactly fuel transfer fail in neurons during metabolic stress, this project will reveal new drug targets to restore lipid-based energy delivery or safely boost backup by glucose-based alternate pathways.
Next Steps for Development:
If successful, we will advance promising interventions — lipid-flux enhancers, LD-mitochondria contact stabilizers, and small molecule glycolytic activators — into testing to assess rescue of movement and cognitive function in rodent models of Parkinson’s disease.