Parkinson’s disease (PD) is a neurodegenerative disorder characterized by fibrillar cytoplasmic aggregates of α-synuclein (i.e., Lewy bodies [LB]) and the associated loss of dopaminergic cells in the substantia nigra. But, mutations in genes such as α-synuclein (SNCA) account for only 10% of PD occurrences. The exposure to environmental toxicants including pesticides (e.g. paraquat [PQ]) and manganese (Mn), are also recognized as important PD risk factors. Thus, aging, genetic alterations and environmental factors all contribute to the etiology of PD. In fact, both genetic and environmental factors are thought to interact in the promotion of idiopathic PD, but the mechanisms involved are still unclear. In this study, we report a toxic synergistic effect between α-synuclein and either paraquat or Mn treatment. We identified an essential role for central carbon (glucose) metabolism in dopaminergic cell death induced by paraquat or Mn treatment that is enhanced by the overexpression of α-synuclein. PQ “hijacks” the pentose phosphate pathway (PPP) to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. PQ also stimulated an increase in glucose uptake, the translocation of glucose transporters to the plasma membrane, and AMPK activation. The overexpression of α-synuclein further stimulated an increase in glucose uptake and AMPK activity, but impaired glucose metabolism. In effect, α-synuclein activity directs additional carbon to the PPP to supply paraquat redox cycling. Alternatively, Mn induces an upregulation in glycolysis and the malate-aspartate shuttle to compensate for energy depletion due to Mn toxicity. Mn treatment causes a decrease in carbon flow through the TCA cycle and a disruption in pyruvate metabolism, which are consistent with a dysfunctional mitochondria and inhibition of pyruvate dehydrogenase. The overexpression of α-synuclein was shown to potentiate Mn toxicity by glycolysis impairment by inhibiting aldolase activity. In effect, α-synuclein overexpression negates the metabolic response to alleviate Mn toxicity that results in an increase in cell death.
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Best,
Dan
The well known challenge with CNS diseases is developing a therapy that can cross the blood-brain barrier. I think our studies also identify an additional challenge, the complexity and diversity of the disease state itself. I think it would be difficult to find the multiple therapies needed to prevent each unique source of Parkinson's disease. Instead, as you point out, we need to look downstream, can we use AMPK activation or some other broad metabolic response to counteract the damage caused by genetic mutations or environmental toxins?
Regarding future directions, there really is multiple avenues we can pursue. I think we need to move to human patients and further establish the results we see in cell cultures and animal models are actually taking place in a Parkinson's patient. Also, I would like to further pursue investigating the cellular compensatory response to these genetic mutations and toxins to see if it can be leveraged as a potential therapy. Of course, there are still details about the molecular mechanisms that still need to be verified and other sources of Parkinson's disease that require investigation. In effect, there is still a lot to do.
