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Glutathione is one of the more important cellular antioxidants. Delivery of glutathione via a range of mechanisms has been tested as a way to improve function in older individuals, with intriguing results in small clinical trials. The benefits include improved mitochondrial function and reduced inflammation. Delivery of antioxidants to mitochondria, where they can suppress the production of reactive oxygen species that takes place as a side-effect of the normal operation of these organelles, has been demonstrated to improve health and modestly slow aging in animal models. Unfortunately glutathione isn’t orally bioavailable; one can’t just take it as a supplement. Intravenous injection works, but the most interesting of the tested delivery methods are iontophoresis patches and daily supplementation with large amounts of the gluthathione precursors glycine and N-acetylcysteine.
In this context, one might take a look at today’s open access paper. It is interesting to see the evidence presented for low glutathione levels to contribute to the development of Parkinson’s disease. The most evident symptoms of the condition derive from cell death in the small but vital population of dopamine-generating neurons. These neurons are evidently more vulnerable to stresses, including oxidative stress deriving from mitochondrial dysfunction, than is the case for other cells in the brain. Glutathione is protective, and the less of it there is, the greater the risk of losing enough dopamine-generating neurons to tip over into the symptoms of Parkinson’s disease.
Aging is the biggest risk factor for Parkinson’s disease (PD), suggesting that age-related changes in the brain promote dopamine neuron vulnerability. It is unclear, however, whether aging alone is sufficient to cause significant dopamine neuron loss and if so, how this intersects with PD-related neurodegeneration. Here, through examining a large collection of naturally varying Drosophila strains, we find a strong relationship between life span and age-related dopamine neuron loss. Strains with naturally short-lived animals exhibit a loss of dopamine neurons but not generalized neurodegeneration, while animals from long-lived strains retain dopamine neurons across age.
Metabolomic profiling reveals lower glutathione levels in short-lived strains which is associated with elevated levels of reactive oxygen species (ROS), sensitivity to oxidative stress and vulnerability to silencing the familial PD gene parkin. Strikingly, boosting neuronal glutathione levels via glutamate-cysteine ligase (Gcl) overexpression is sufficient to normalize ROS levels, extend life span, and block dopamine neurons loss in short-lived backgrounds, demonstrating that glutathione deficiencies are central to neurodegenerative phenotypes associated with short longevity.
These findings may be relevant to human PD pathogenesis, where glutathione depletion is reported to occur in idiopathic PD patient brain through unknown mechanisms. Building on this, we find reduced expression of the Gcl catalytic subunit in both Drosophila strains vulnerable to age-related dopamine neuron loss and in human brain from familial PD patients harboring the common LRRK2 G2019S mutation. Our study across Drosophila and human PD systems suggests that glutathione synthesis and levels play a conserved role in regulating age-related dopamine neuron health.
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