It is known that Parkinson’s disease, the second most common neurodegenerative disease, has genetic causes in 15% of cases. It has been shown that premature aging of dopaminergic neurons in the substantia nigra in the brain is the reason for the motor symptoms that characterise this disease. However, how this happens is not yet fully understood. Now, as study from researchers led by the University of Luxembourg shows how the defective DJ1 (PARK7) gene causes premature aging of neurons in Parkinson’s patients. The team state that the genetic defect causes changes in the cellular metabolism meaning that neurons are subjected to oxidative stress and an increased immune response in the brain. The opensource study is published in the journal Neurobiology of Disease.
Previous studies show that DJ1 is expressed in different organs throughout the body and was first identified as an oncogene together with activated Ras. While DJ1 over-expression provokes oncogenesis, loss of function mutations in DJ1 have also been associated with a familial autosomal recessive form of Parkinson’s disease with an early onset of disease progression. Although there is evidence that DJ1 regulates metabolism, a detailed understanding of its role in central metabolism, especially in the context of Parkinson’s disease, is still missing. The current study investigates a specific form of Parkinson’s disease with the defective DJ1 gene.
The current study investigated the metabolism of neurons lacking DJ1 and discovered that two key metabolic pathways were affected. Results show that without DJ1, neurons cannot absorb enough glutamine and this affects serine production; both amino acids are important for producing glutathione, which is used to neutralise free radicals. Data findings show that in the absence of DJ1, this defence mechanism does not work effectively and oxidative stress occurs, prematurely aging the cells.
Results show that mutations in the DJ1 gene can also negatively affect microglial cells, which become ‘hyperactive’ when the DJ1 gene is defective. The group explain that normally, microglial cells are only activated when something in the brain needs to be cleaned up, for instance during inflammation. However, data findings show that if these cells are constantly active, as with the DJ1 defect, this weakens underlying neurons. Interestingly, the researchers were able to determine metabolic changes in the brain’s immune cells and in the blood of Parkinson’s patients with mutant DJ, which could lead to new diagnostic avenues in the future.
The team surmise that the changes described in glutamine and serine metabolic processes could thus be used to develop novel approaches for treating Parkinson’s. For the future, the researchers state that the next step will involve investigating how affected metabolic pathways can be influenced using drugs.
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