High levels of corticosterone — a hormone that regulates energy, immune, and stress responses — is a risk factor for the development and progression of Parkinson’s disease, according to a mouse study.
The study, “Chronic corticosterone aggravates behavioural and neuronal symptomatology in a mouse model of alpha-synuclein pathology,” was published in the journal Neurobiology of Aging.
Parkinson’s disease is a neurodegenerative disorder mainly resulting from the gradual loss of dopaminergic neurons in the substantia nigra, a region of the brain responsible for controlling body movements.
This is a consequence of overproduction and misfolding of the protein alpha-synuclein in neurons, which leads to the formation of small toxic deposits called Lewy bodies that gradually damage and kill nerve cells. Growing evidence has demonstrated that these alpha-synuclein aggregates are associated with Parkinson’s onset and progression.
“Injection of alpha-synuclein preformed fibrils (PFFs) in different brain regions … induces pronounced alpha-synuclein pathology [aggregate] propagation. Interestingly, in these [mouse] models the amygdala is among the brain regions most severely affected by alpha-synuclein pathology [disease],” the researchers wrote.
The amygdala is an area of the brain involved in memory, decision-making, and emotional responses. Several non-motor symptoms in Parkinson’s, including anxiety and depression, have been linked to structural alterations and functional impairments of the amygdala.
“Similarly, chronic stress and glucocorticoid [imbalance] change amygdala physiology [function], and indeed are involved in the development of anxiety and depression,” they wrote.
The group of researchers from the Brain Mind Institute at the École Polytechnique Fédérale de Lausanne in Switzerland set out to investigate if mood/emotional alterations linked to amygdala dysfunction might accelerate the formation and propagation of alpha-synuclein aggregates associated with Parkinson’s in a mouse model of the disease.
To test their hypothesis, they first treated mice with corticosterone, a glucocorticoid that is normally produced in response to stress, to mimic the effects of depression and chronic stress in the amygdala.
Animals were then injected on one side of the brain’s striatum — a region involved in motor and cognitive control — with either alpha-synuclein preformed fibrils to trigger the formation and propagation of alpha-synuclein aggregates across the whole brain, or with a saline solution (vehicle control).
Chronic treatment with corticosterone triggered depression in animals and had a strong effect on their body shape, fat deposition, body weight, and drinking and eating habits. Injection of alpha-synuclein preformed fibrils had no effects on any of these parameters.
Behavioral tests performed one to two months after the injection of alpha-synuclein showed that animals that had been injected with these fibrils displayed mild anxiety, which was reversed by corticosterone treatment.
However, they found that chronic treatment with corticosterone in animals that had been injected with preformed fibrils led to the accumulation of phosphorylated alpha-synuclein in specific regions of the brain, including the entorhinal cortex, a region involved in memory, spatial navigation, and time perception.
Alpha-synuclein phosphorylation is a chemical modification in which a phosphate group is added to the protein. It is known to occur in Parkinson’s disease, and is thought to be a critical step in disease progression, as it enhances alpha-synuclein’s toxicity, possibly by increasing the formation of aggregates.
They also discovered that treatment with corticosterone in mice that had been injected with alpha-synuclein fibrils increased the loss of dopaminergic neurons.
“We report aggravated alpha-synuclein pathology [disease] and neurodegeneration in mice injected with alpha-synuclein [preformed fibrils] in a condition of heightened corticosterone, suggesting heightened glucocorticoid levels as a risk factor for the development of the neuropathological hallmarks of Parkinson’s disease and potential target for treatment,” the researchers wrote.
“Further studies aimed at elucidating the vulnerability factors of specific brain regions to alpha-synuclein pathology, and why at some point resilience fails and neurodegeneration (such as in the substantia nigra) occurs, are needed and will greatly enhance our understanding of the role of alpha-synuclein pathology in the [development] of Parkinson’s disease and synucleinopathies,” they added.
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