Parkinson’s rat model accounts for genetic, environmental risk factors
'Double-hit' model should help show interaction that leads to disease in people
Researchers have developed a “double-hit” rat model of Parkinson’s disease wherein neurodegeneration is driven by both genetic susceptibility and environmental exposure to toxins.
The rats were genetically engineered to accumulate human alpha-synuclein protein in the brain like existing models, but were also injected with an inflammation-inducing toxin. The animals developed neurodegeneration more like what’s seen in Parkinson’s patients relative to rats that only had a genetic susceptibility. The scientists believe the rats will offer a reliable model to study how multiple factors interact to lead to Parkinson’s disease in people.
The study, “Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human alpha synuclein,” was published in npj Parkinson’s Disease.
Parkinson’s disease features the progressive loss of nerve cells, called dopaminergic neurons, responsible for producing the brain signaling chemical dopamine. What triggers the loss of these cells isn’t known, but it’s believed to be a process that includes genetic risk factors, environmental exposures, and other biological influences.
A hallmark of Parkinson’s is the formation of toxic clumps of alpha-synuclein, which is believed to contribute to neurodegeneration. Neuroinflammation is also usually evident, although its role in driving neurodegeneration isn’t established.
Animal models used to study Parkinson’s often house alterations in the SNCA gene that encodes alpha-synuclein production. Mutations in the gene are a known cause of familial Parkinson’s.
There’s no one animal model that completely replicates the condition in people, however, and many models fail to develop the neurodegeneration seen in patients. This is because they don’t account for the environmental factors that might also contribute to neurodegeneration, the researchers said.
Accounting for genetic and environmental factors
Here, researchers sought to develop a so-called “double-hit” model that had both genetic and environmental underpinnings.
The rats were first genetically engineered to overexpress the human SNCA gene, which resulted in alpha-synuclein accumulation. They were then injected with lipopolysaccharide (LPS), a toxin from bacteria that’s often used to elicit inflammatory responses.
Toxin exposure is one of the environmental factors believed to contribute to Parkinson’s and research indicates LPS can lead to Parkinson’s-like symptoms in animal models.
The double-hit rats developed long-lasting increases in markers of immune cell activation, reflecting an inflammatory state. This appeared to involve microglia, the brain’s resident immune cells, as well as other types of immune cells normally found in circulation.
As expected, the SNCA genetic alteration led to disease-associated forms of alpha-synuclein accumulating in the brain and the LPS seemed to further exacerbate that in certain brain regions.
While rats with only SNCA over-expression didn’t develop dopaminergic neurodegeneration, the second hit with the LPS injection led to a loss of dopaminergic neurons in the substantia nigra, the brain region where these cells are also lost in people with Parkinson’s.
Moreover, dopaminergic neurons in the double-hit rats lost dendrites, the branches they normally use to connect and communicate with other cells, and exhibited reduced dopamine release.
Interestingly, the rats didn’t exhibit common symptoms of Parkinson’s disease, including altered motor behaviors or depression-like symptoms.
This finding “may not be surprising,” given that even in Parkinson’s patients, neurodegeneration has usually progressed significantly before these symptoms become evident, said the researchers, who called the rats a reliable model for investigating how genetic and environmental factors interact to drive neurodegeneration in Parkinson’s. The findings support the so-called “dual-hit hypothesis” for Parkinson’s, “whereby elevated endotoxin under a genetic predisposition may interact or synergize, driving the neurodegenerative processes that underlie …[Parkinson’s disease].”
Another takeaway from the study is that inflammation might play a significant role in contributing to Parkinson’s neurodegeneration.
“Our findings provide additional evidence for the role of the immune system in playing a key role in the onset and progression of [Parkinson’s disease],” wrote the researchers, who said more studies are needed to better examine the source of the immune cell populations that may be involved in this response and whether LPS-induced inflammation actually exacerbated neurodegeneration or simply accelerated damage that would normally be seen later on.
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