The pathogenic relationship of Alpha Synuclein and Mitochondrial dysfunction in sporadic Parkinson's Disease

Abstract

Parkinson s Disease (PD) is a complex neurodegenerative disorder and a lack of knowledge of the molecular mechanisms responsible for the cause and progression of PD is a major impediment to therapeutic advances. The protein Alpha-Synuclein (αSyn) is a central component in PD pathogenesis, with its increased expression resulting in early onset forms of PD, yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD.

An unbiased screen in Saccharomyces cerevisiae identified a number of OXPHOS genes whose deletion sensitised cells to the induced expression of αSyn. Only the combination of partial OXPHOS inhibition and αSyn expression resulted in toxicity and cell death. A similar synergistic relationship was observed in a mammalian PD model of low levels of αSyn expression as the combination of partial OXPHOS inhibition produced a significantly greater amount of cell death after 4 days than the sum of either insult alone.

A number of cellular stresses have been observed in PD patients and further investigation into the nature of this αSyn-OXPHOS synergistic relationship has discovered a cellular cascade of events unique to the presence of both these insults in combination. In yeast and mammalian models of PD, the αSyn-OXPHOS model results in early initiation of endoplasmic reticulum (ER) stress, nitric oxide (NO) species, cholesterol dysregulation and OXPHOS dysfunction. These events are followed by the production of reactive oxygen species and cell death. An ER stress inhibitor, sterol inhibitor or NO inhibitor reduced cell death, displaying a potential functional role of these stresses in PD development. A sterol inhibitor reduced αSyn protein levels, implicating the reduction of cholesterol as a potential therapeutic target.

This model proposed that mitochondrial dysfunction and αSyn toxicity may exacerbate each other in a self-amplifying cycle that, chronically, could attain a level of damage to cause the observed pathology and account for the late onset nature of the disease. Currently there is no cure or early diagnosis for PD, where intervention strategies could be implemented. Discovering these early events may assist in the identification of biomarkers and early preventative treatment strategies for PD.