Novel Parkinson's Therapies Possible with New Mouse Model

Parkinson’s disease (PD) is a neurodegenerative disorder that is marked by the accumulation of the protein, α-synuclein (αS), into clumps known as Lewy bodies, which diminish neural health. Now, researchers from Brigham and Women’s Hospital (BWH) report the development of a mouse model to induce PD-like αS aggregation, leading to resting tremor and abnormal movement control. The mouse responds to L-DOPA, similarly to patients with PD.

The team’s study (“Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson’s Disease”) on the use of this transgenic mouse model appears in Neuron.

“α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in PD. Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E→K mutations in adjacent KTK EGV motifs,” write the investigators.

“This tetramer-abrogating mutant causes phenotypes similar to PD. αS monomers accumulate at membranes and form vesicle-rich inclusions. αS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controlling motor behavior, including a decrease in nigrostriatal dopaminergic neurons. The outcome is a progressive motor syndrome including tremor and gait and limb deficits partially responsive to L-DOPA. This fully penetrant phenotype indicates that tetramers are required for normal αS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications.”

“It is difficult to find efficient treatment therapies that target αS aggregation,” says lead author Silke Nuber, Ph.D., an instructor in the Ann Romney Center for Neurologic Diseases at BWH. “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-phenotype, to better understanding the mechanisms that lead to the initiation of PD.”

In a healthy brain, this lab first reported (Bartels et al, Nature 2011) that αS can occur normally in the form of helically folded tetramers (four units of αS wound around each other), a form that resists the aggregation that abnormal αS monomers undergo. To model the brain in PD, Dr. Nuber and her team created a novel transgenic mouse that has a tetramer-lowering mutation, which leads to αS deposits, loss of dopamine and neurotoxicity.

“With these new mice, we set out to examine the upstream role of tetramer-lowering mutations and their relevance to PD,” Dr. Nuber says. “Our hypothesis was that upstream destabilization of normal tetramers to excess monomers can lead to the changes of PD.”

To examine the effect of tetramer-abrogating mutations on αS pathology, the research team created multiple mouse lines with certain αS mutations that chronically decrease the tetramers, increase free monomers and lead to neuronal dysfunction and degeneration. They then compared their new tetramer-abrogating mouse to a mouse expressing normal human αS protein and a mouse with just a single familial PD αS mutation. The mice were carefully evaluated side-by-side for key biochemical, histological, and behavioral characteristics associated with PD.

The new tetramer-abrogating mouse displayed key PD-like changes, including age-dependent αS aggregation in altered neurons and distinctive abnormal movements. These changes were all derived from preventing normal αS tetramer formation. These findings strongly suggest that tetramers are required for the normal state of αS in the brain. The authors conclude that it is likely that shifting tetramers to monomers can initiate PD. They also note that the phenotype was more prominent in male mice, which is reminiscent to what occurs in PD, a finding they plan to follow up on within the framework of the Women’s Brain Initiative at BWH.

“We can now examine PD in a whole new light. We can think about stabilizing the physiological αS tetramer, an entirely novel therapeutic concept, as a means of preventing or delaying the onset of PD,” says Dr. Nuber.

“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,” says Dennis Selkoe, M.D., the senior author of the paper and the co-director of the Ann Romney Center for Neurologic Disease at BWH. “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.”