Researchers at the Buck Institute for Research on Aging have learned that oxidative stress, a main driver in sporadic Parkinson’s Disease, affects the parkin protein – essential to clear damaged proteins and mitochondria in cells – in the same manner that genetic mutations do.
The findings help researchers better understand sporadic PD. The molecular dysfunction identified may constitute a promising target for drug development.
The research paper, “Detrimental effects of oxidative losses in parkin activity in a model of sporadic Parkinson’s disease are attenuated by restoration of PGC1 alpha,” was published in Neurobiology of Disease.
Researchers focused on the parkin protein, known to play a role in the degradation of damaged or unneeded proteins and also thought to be involved in the maintenance of mitochondrial function. It is encoded by the PARK2 gene, whose mutations have been identified as causes of familial Parkinson’s Disease.
The pathology is characterized by the accumulation of damaged protein and mitochondria due to loss of cells’ recycling ability. It ultimately leads to damage in nerve cells and neurodegeneration.
The new research led by Julie Andersen, demonstrates that oxidative stress, central to sporadic forms of PD, causes similar damage to the parkin protein that is observed when mutations are present.
“This gives us a significant insight into sporadic PD which accounts for 95% of all cases of the disease,” Andersen said. “We also determined that the signaling pathway involved in the molecular dysfunction is a good target for drug development.”
Researchers identified two major regulatory proteins in the pathway, PGC-1alpha, which affects the synthesis of new mitochondria, and TFEB, which is involved in breaking down old mitochondria. Following oxidative stress, both proteins were found to be down-regulated. The scientists found that increasing the expression of PGC-1alpha in affected mice led to the normalization of mitochondria function and prevention of degeneration of dopaminergic neurons affected by PD.
Researchers are now screening compounds in human cell cultures and worms modeling PD. They are seeking compounds that target the pathway and prevent neurotoxic damage.
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