New study associates oxidative stress with the spread of aberrant proteins

Oxidative stress may play a driving role in the spread of aberrant proteins involved in Parkinson's disease. This is the result of laboratory studies conducted by researchers at the German Center for Neurodegenerative Diseases (DZNE). The results are published in the "Journal of Clinical Investigation".

Parkinson's disease is a neurodegenerative disease whose clinical manifestations include motor symptoms (eg, tremor and slow movement) as well as non-motor symptoms (eg, sleep disturbances and depression). At the microscopic and pathological level, the disease is characterized by an accumulation of abnormal intraneuronal inclusions. They are formed as a result of the aggregation of a protein called "alpha-synuclein". During the course of the disease, these inclusions gradually appear in various regions of the brain, contributing to the gradual exacerbation of the severity of the disease. The mechanisms behind this growing pathology are poorly understood. Research by DZNE scientists now indicates that "oxidative stress," that is, excessive and uncontrolled production of reactive oxygen species, could play an important role in the pathological spread of oxygen. alpha-synuclein. The results are based on in vivo studies in mice and in vitro experiments on cells in culture.

"It has long been considered that oxidative stress is implicated in the pathogenesis of Parkinson's disease, but our work reveals a new intriguing mechanism that can link oxidative stress to disease development, and we show that under oxidative stress, propensity of alpha-synuclein to "travel" from one neuron to another is considerably improved, thus facilitating the exchange of harmful protein species, the occurrence of a pathology and the spread of this pathology in the brain, "said Professor Donato Di Monte, scientist of the DZNE, at the head of the research journal.

He adds: "Although, in our study, we artificially induced oxidative stress in laboratory models, we know that an increase in the production of deleterious oxygen species could occur in the Parkinson's Brain It could be caused by various conditions, such as genetic mutations and environmental exposures Parkinson's disease is an aging-related disease that makes it very likely that aging brain cells become more vulnerable to pathological processes involving stress oxidative. "

Experimental framework

In a series of experiments, Di Monte and colleagues studied mice producing alpha-synuclein in a specific brain region, namely the spinal cord dorsal, known to be a primary target of the pathology of alpha-synuclein. synuclein in Parkinson's disease. Under these conditions, researchers were able to show oxidative stress, the formation of small aggregates of alpha-synuclein (called oligomers) and neuronal damage. The increased production of alpha-synuclein has also led to its "jump" of oblong medulla donor neurons into receptor neurons in neighboring brain regions that have become affected by the accumulation and aggregation of cells. Progressive alpha-synuclein. It is interesting to note that the treatment of mice with paraquat, a chemical agent generating significant amounts of reactive oxygen species and thus causing oxidative stress, exacerbates the pathology of the disease. alpha-synuclein and causes its more pronounced spread in the brain.

"Our results support the hypothesis that a vicious cycle could be triggered by an increased load of alpha-synuclein and oxidative stress," Di Monte said. "Oxidative stress could promote the formation of alpha-synuclein aggregates, which in turn could exacerbate oxidative stress." Moving from neuron to neuron, this toxic process could affect more and more regions of the brain and contribute to the progression of pathology and the disappearance of neurons. "

Abnormal proteins

The precise mechanisms underlying the increased neuron transfer to alpha-synuclein in the presence of oxidative stress are not fully understood. However, more detailed badyzes by Di Monte and colleagues, including in vitro experiments, have revealed the formation and accumulation of abnormal forms of alpha-synuclein that have been oxidized and nitrated as a result of oxidative stress. These abnormal protein species have been shown to be particularly mobile and more likely to move from donor cells to recipient cells.

"The identification of toxic species of alpha-synuclein with a high propensity for aggregation and spread has important implications," said Di Monte. "They could be targeted by a therapeutic intervention that can prevent the early development of the disease and / or thwart the progression of the disease at more advanced stages of the disease."