Similar to Parkinson’s patients, this model also responds to levodopa, one of the main compounds used to treat symptoms of the disease.
The study, “Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease,” was published in the journal Neuron.
“It is difficult to find efficient treatment therapies that target αS [alpha-synuclein] aggregation,” Silke Nuber, PhD, from the Brigham and Women’s Hospital (BWH) in Boston and the study’s first author, said in a press release. “Thus, it is necessary to develop mouse models that reflect the long-term changes, including Lewy-like aggregation of αS and an associated close PD [Parkinson’s disease]-phenotype, to better understand the mechanisms that lead to the initiation of PD.”
The brains of Parkinson’s patients are characterized by the accumulation of a protein called alpha-synuclein into clumps known as Lewy bodies. This accumulation affects nerve cells, causing them to die.
Alpha-synuclein plays a key role in a healthy brain, regulating the release of synaptic vesicles — “bubbles” filled with chemical neurotransmitters (messengers) that are released between nerve cells or between nerve cells and their effector cells, such as those in the muscle.
This regulation occurs when alpha-synuclein is in its healthy state, i.e., arranged in a tetramer — four units of the protein wrapped around each other.
In familial cases of Parkinson’s disease, patients may carry mutations in the alpha-synuclein gene that contribute to the clumping of alpha-synuclein by shifting tetramers to aggregation-prone monomers — when the natural tetramer structure is replaced by single-protein chains, or monomers.
This causes the death of dopamine producing-nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, a critical signaling molecule that regulates brain cell activity and function.
Researchers at BWH have now developed a new transgenic mouse model that carriers a mutant form of alpha-synuclein — what they call a tetramer-lowering mutation — to understand its contribution to the disease.
Specifically, researchers engineered several mouse lines carrying different alpha-synuclein mutations that impact the natural tetramer structure of the alpha-synuclein protein, mimicking what occurs in familial cases of the disease.
“With these new mice, we set out to examine the upstream role of tetramer-lowering mutations and their relevance to PD,” Nuber said. “Our hypothesis was that upstream destabilization of normal tetramers to excess monomers can lead to the changes of PD.”
They compared their newly developed mouse model with mice expressing a functional alpha-synuclein protein (wild-type mice) and with mice carrying a single mutation in the alpha-synuclein gene, typically found in familial cases of Parkinson’s disease.
Researchers evaluated the animals’ behavioral features, along with conducting molecular and tissue analysis.
The new tetramer-abrogating mouse model developed spontaneous behavioral changes typical of Parkinson’s disease, including abnormal gait and gradual worsening of head and body tremor. None of these features were detected in the wild-type healthy mice.
These motor deficits were more prominent in male mice, a phenomenon also observed in Parkinson’s patients.
The loss of alpha-synuclein tetramer structural organization led to the accumulation of the protein’s monomers that resulted in the degeneration of dopaminergic neurons in the brain cortex, specifically in a region called the substantia nigra— one of the main regions affected in Parkinson’s — and triggered the progressive loss of motor function.
Importantly, just like in humans, motor deficits in these mice were improved upon treatment with Parkinson’s therapy levodopa, also called L-DOPA.
These findings suggest that the tetramer structure of alpha-synuclein is required for a healthy brain, and that loss of its structure may contribute to Parkinson’s disease onset.
“We can now examine PD in a whole new light. We can think about stabilizing the physiological αS [alpha-synuclein] tetramer, an entirely novel therapeutic concept, as a means of preventing or delaying the onset of PD,” Nuber said.
“With our lab’s experience in deciphering the earliest stages of Alzheimer’s disease, we decided some time ago to apply analogous approaches to the different protein abnormality occurring in PD,” said Dennis Selkoe, MD, the study’s lead author.
“We believe this unique mouse model shows that the tetrameric form of αS we discovered in 2011 is necessary for normal neuronal function, so that abrogating the tetramer has direct PD-like consequences. This PD mouse model will provide a new route to entirely novel therapeutic approaches,” said Selkoe, who is also the co-director of the Ann Romney Center for Neurologic Disease at BWH.