Oxidative Stress in the Aging Brain Accelerates the Spread of α-synuclein

Parkinson's disease, like many neurodegenerative conditions, is associated with the age-related aggregation of a specific protein, in this case α-synuclein. The protein aggregates have a halo of harmful biochemistry, causing dysfunction and cell death in neurons. Researchers here propose that the increased levels of oxidative stress observed in old tissues spur the spread of α-synuclein protein aggregates from cell to cell as the disease progresses. Oxidative stress can arise from mitochondrial dysfunction, as mitochondria produce oxidative molecules as a byproduct of their normal operation, but is also associated with chronic inflammation. Both are also features of aging and thought to be important in the progression of neurodegenerative conditions.

At the microscopic and pathological levels, Parkinson's disease is characterized by accumulation of abnormal intraneuronal inclusions. They are formed as a result of aggregation of a protein called α-synuclein. In the course of the disease, these inclusions progressively appear in various brain regions, contributing to the gradual exacerbation of disease severity. The mechanisms behind this advancing pathology are poorly understood. Research now indicates that oxidative stress, i.e. an excessive and uncontrolled production of reactive oxygen species, could play an important role in the pathological spreading of α-synuclein.

In a series of experiments, researchers studied mice that overproduced α-synuclein in a specific brain region, namely the dorsal medulla oblongata, known to be a primary target of α-synuclein pathology in Parkinson's disease. Under this condition, the researchers were able to show oxidative stress, formation of small α-synuclein aggregates (so called oligomers) and neuronal damage. Increased production of α-synuclein also led to its "jump" from donor neurons in the medulla oblongata into recipient neurons in neighboring brain regions that became affected by progressive α-synuclein accumulation and aggregation.

Interestingly, treatment of mice with paraquat, a chemical agent that generates substantial amounts of reactive oxygen species and thus triggers an oxidative stress, exacerbated α-synuclein pathology and resulted in its more pronounced spreading throughout the brain. "Our findings support the hypothesis that a vicious cycle may be triggered by increased alpha-synuclein burden and oxidative stress. Oxidative stress could promote the formation of alpha-synuclein aggregates which, in turn, may exacerbate oxidative stress. Jumping from neuron to neuron, this toxic process could affect more and more brain regions and contribute to progressive pathology and neuronal demise."

Link: https://www.dzne.de/en/news/public-relations/press-releases/press/detail/parkinsons-a-new-study-associates-oxidative-stress-with-the-spreading-of-aberrant-proteins/


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