Oxidative Stress Seen Promote Spread of Toxic Alpha-Synuclein Across Cells, Possibly Trigger Disease

Oxidative stress may be a trigger for Parkinson’s and can promote its progression by facilitating the spread of toxic alpha-synuclein protein across cells, researchers report.

Their study, “Oxidative stress in vagal neurons promotes parkinsonian pathology and intercellular α-synuclein transfer,” was published in the Journal of Clinical Investigation.

Parkinson’s is characterized by a buildup of the protein alpha-synuclein in the brain, which forms clumps known as Lewy bodies that damage and kill nerve cells.

Although Parkinson’s trigger remains to be identified, research indicates its causative mechanism involves genetics, problems in mitochondria (energy “powerhouses” of cells), and oxidative stress — an imbalance between the production of harmful free radicals and the ability of cells to detoxify, resulting in cellular damage. Taken together, these molecular and cellular changes eventually kill dopamine-producing neurons, the nerve cell type gradually lost in Parkinson’s disease.

Scientists at the German Center for Neurodegenerative Diseases (DZNE) investigated the relationship between oxidative stress, neurodegeneration, and alpha-synuclein pathology.

A single injection of adeno-associated viral vectors (AAVs) carrying human alpha-synuclein DNA was administered into the dorsal motor nucleus of the vagus nerve of mice, leading to protein aggregation and neuron-to-neuron transmission of alpha-synuclein. Mice also showed selective degeneration in cells that received the human alpha-synuclein DNA. (The vagus nerve is a brain region involved in movement control, and a primary site of Lewy body accumulation.)

The animals were then given paraquat, a toxic and fast-acting herbicide that’s capable of producing great amounts of free radicals, replicating oxidative stress in a laboratory setting.

Results showed that acetylcholine-producing neurons — which, along with dopaminergic neurons, are affected in Parkinson’s — of the dorsal motor nucleus of the vagus nerve were particularly susceptible to oxidative stress. The AAV injection alone induced oxidative stress, and those levels significantly increased with paraquat. These molecular changes led to the production of modified forms of alpha-synuclein, increased clump formation, and neuronal degeneration within the dorsal motor nucleus of the vagus nerve.

Higher levels of oxidative stress influenced neuron-to-neuron alpha-synuclein transfer and greater protein spread from the dorsal motor nucleus of the vagus nerve toward rostal brain regions (more frontal regions).

To further investigate alpha-synuclein’s spreading behavior, human neurons with alpha-synuclein were grown in the lab in different concentrations of paraquat. Pro-oxidant conditions were found to increase alpha-synuclein’s propensity to move from cell to cell.

Importantly, scientists identified nitrated forms of the protein as highly transferable molecules, supporting the hypothesis that oxidized or nitrated forms of alpha-synuclein have pronounced cell-to-cell mobility.

Like oxidative stress (involving reactive oxygen species), nitrative stress (involving nitrogen molecules) has been implicated in Parkinson’s. This oxidative/nitrative stress is known to provoke harmful changes in alpha-synuclein’s structure, and nitrated forms of the protein have been found in the brain, gastrointestinal tract, and blood cells of Parkinson’s patients.

“Oxidative stress has long been considered to be involved in the pathogenesis of Parkinson’s disease. Our work, however, reveals a new intriguing mechanism that may link oxidative stress to disease development,” Donato Di Monte, MD, a senior DZNE scientist and the study’s main researcher, said in a press release.

“We show that under oxidative stress the propensity of alpha-synuclein to ‘travel’ from one neuron to the other is significantly enhanced, thus facilitating the exchange of harmful protein species, occurrence of pathology and the spreading of this pathology throughout the brain,” Di Monte added.

Overall, this work suggests that cell-to-cell spread of alpha-synuclein is enhanced by oxidative stress and, as such, this stress could trigger and promote Parkinson’s disease.

“These findings substantiate the relevance of oxidative injury in PD [Parkinson’s disease] pathogenetic processes, establish a relationship between oxidative stress and vulnerability to α-synuclein pathology and define a new mechanism, enhanced cell-to-cell α-synuclein transmission, by which oxidative stress could promote PD development and progression,” the study concluded.