Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span

Authors: COLEMAN, COLIN - Oregon Health & Science University; PALLOS, JUDIT - Oregon Health & Science University; ARREOLA-BUSTOS, ALICIA - Oregon Health & Science University; WANG, LU - University Of Washington; RAFTERY, DANIEL - University Of Washington; PROMISLOW, DANIEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MARTIN, IAN - Oregon Health & Science University

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/4/2024
Publication Date: 10/10/2024
Citation: Coleman, C.R., Pallos, J., Arreola-Bustos, A., Wang, L., Raftery, D., Promislow, D., Martin, I. 2024. Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span. Proceedings of the National Academy of Sciences (PNAS). https://doi.org/10.1073/pnas.2403450121.
DOI: https://doi.org/10.1073/pnas.2403450121

Interpretive Summary: There are many theories that try to explain why some individuals live longer than others. To address this question, this study started from the observation that age is the greatest risk factor for Parkinson's disease, which is caused by failure in dopamine neurons. In a comparison of 15 short-lived strains and 15 long-lived strains in the fruit fly, Drosophila melanogaster, we asked if the short-lived strains tend to have higher than average loss of dopamine neurons. We found that this is, indeed, the case. We also found that these strains had relatively low levels of the chemical glutathione, and higher than average levels of "reactive oxygen species", which are unstable molecules that can cause damage in cells. Strikingly, when we increased levels of glutathione by altering a specific genetic pathway, we were able to increase lifespan, and block the loss of dopamine neurons that occurred in short lived strains. Our findings led us to ask about this same genetic pathway in brains from Parkinson's disease patients, where we found the same mutation as in fly strains vulnerable to age-related loss of dopamine neurons. Our work underscores not only the importance of dopamine neuron loss in shaping aging, at least in certain genetic backgrounds, but also the value of the fruit fly as a powerful model for studying the genetic basis of natural variation in aging.

Technical Abstract: 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 without 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 the 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 the 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.