Natural Variation in Age-Related Dopamine Neuron Degeneration is Glutathione-Dependent and Linked to Life Span.

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 strains, we find a strong relationship between life span and age-related dopamine neuron loss. Naturally short-lived strains exhibit a loss of dopamine neurons but not generalized neurodegeneration, while 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 . 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 frequently reported in idiopathic PD patient brain. Building on this evidence, we detect reduced levels of GCL catalytic and modulatory subunits in brain from PD patients harboring the LRRK2 G2019S mutation, implicating possible glutathione deficits in familial LRRK2-linked PD. Our study across and human PD systems suggests that glutathione plays an important role in the influence of aging on PD neurodegeneration.