Reduced Antioxidant Protection Leads to Neuron Loss in Parkinson's Disease

Lack of antioxidant protection in brain cells due to mutations that prevent the expression of the protein encoded by the oncogene DJ-1 (also known as Parkinson protein 7 or PARK7) has been linked to premature aging of neurons in Parkinson's disease patients.

The oncogene DJ-1 was identified originally as a suppressor of PTEN (phosphatase and tensin homolog), and loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). While it was known that DJ-1 had an important function in cellular antioxidant responses, its role in the central metabolism of neurons remained to be clarified.

Investigators at the University of Luxembourg (Esch-sur-Alzette, Luxembourg) applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1.

They reported in the February 1, 2016, online edition of the journal Neurobiology of Disease that DJ-1 deficient neuronal cells exhibited decreased glutamine influx and reduced serine biosynthesis. These two metabolic pathways provide the precursors glutamate, serine, and glycine for de novo synthesis of glutathione. In line with these metabolic flux changes, the investigators observed decreased glutathione levels and an impaired antioxidant response in DJ-1 deficient cells.

In addition, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered antioxidant metabolism and constitutive activation of glia cells raised the susceptibility of dopamine-producing neurons towards degeneration in patients harboring mutated DJ-1.

"Normally, microglial cells are only activated when something in the brain needs to be cleaned up, for instance during inflammation," said senior author Dr. Karsten Hiller, head of the metabolomics group at the University of Luxembourg. "However, if these cells are constantly active, as we discovered happens with the DJ-1 defect, this weakens the underlying neurons. We need the right amount of DJ-1. While in some forms of cancer there is too much DJ-1, in this case of Parkinson's disease, neurons do not have enough DJ-1 and die off."

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