New mouse model provides key insights into Parkinson’s disease

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To understand and develop treatments for complex genetic diseases, researchers rely upon animal models – an important tool that reproduces features of a disease in a model organism in order to avoid risks to humans. However, the process of creating an animal model comes with a conundrum: how do you construct models of diseases that we know so little about?

In a paper published earlier this year in The Journal of Neuroscience, Xiaoxi Zhuang, PhD, professor of neurobiology, and his colleagues tackled this challenge by developing a new mouse model that expresses a mutant human gene involved in Parkinson’s disease. Their novel approach induces the loss of dopamine-producing neurons in mice, mimicking symptoms of the disease in a controllable way. The model has already produced surprising results, including insights into how damaged mitochondria contribute to Parkinson’s, and serves as a powerful system to test new therapeutics for the disease.

Xiaoxi Zhuang, PhD, professor of neurobiology

Xiaoxi Zhuang, PhD, professor of neurobiology

“We have generated a transgenic mouse line with a Parkinson’s disease-causing mutant gene, overexpressed in dopamine neurons, in an inducible and reversible manner,” said Zhuang, who is senior author on the study. “In addition, previous studies have shown that mitochondria dysfunction and abnormalities in their removal may play a role in Parkinson’s, but very few were in whole animals. It is truly exciting that we were able to demonstrate this in mice.”

Parkinson’s disease is a neurodegenerative disorder characterized by the death and malfunction of neurons that produce the neurotransmitter dopamine. The dramatic loss of these neurons causes a ripple effect throughout the body – the most recognizable symptom being tremors and the deterioration of motor skills.

To shed light on the molecular mechanisms that can lead to Parkinson’s, Zhuang and his colleagues genetically engineered mice to produce a mutant version of a human protein called α-synuclein (A53T). High levels of A53T in dopamine neurons cause cell death, but turning off A53T production reverses this process. By controlling A53T levels, the researchers were able to induce and subsequently reverse dopamine neuron loss. This is first time this has been possible in a mammalian system.

A key observation in studying the death of dopamine neurons in this model was the appearance of damaged mitochondria – important cellular structures that function as the powerhouse of the cell.

“Before degeneration, dopamine neurons show profound mitochondria abnormalities,” Zhuang said, “This is characterized by mitochondria with altered morphology and pathological inclusions containing mainly damaged mitochondria.”

Further testing implicated two other genes, previously shown to be involved in Parkinson’s, that are known to produce mitochondrial defects. The deletion of these two genes, parkin and PINK1, lead to mitochondrial dysfunction in flies; but the effect of deleting them have yet to be seen in a mammalian organism, until now.

In their study, Zhuang’s team “found that genetic deletion of either parkin or PINK1 in human α-synuclein A53T overexpression mice significantly worsened mitochondrial pathologies, including drastically enlarged inclusions and loss of total mitochondria contents.” These mitochondrial abnormalities implicate the function of parkin and PINK1 in the death of cells over-producing A53T.

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Electron microscopy reveals abnormalities in dopamine-producing neurons in the new mouse model. These senescent mitochondria showed the disordered cristae, swollen matrix, and disappearance of outer membranes (arrowhead). In contrast, mitochondria with normal appearance were found in the neighboring cells (arrow).

It is thought that parkin and PINK1 play roles in clearing damaged mitochondria from the cell, a process known as autophagy. The loss of dopamine neurons in these mouse models are much worse due to the combination of two factors – toxic levels of the mutant A53T protein causes mitochondrial abnormalities, and the loss of parkin or PINK1 causes less efficient removal of damaged mitochondria.

“Our data suggest that mitochondria are the main targets of toxic mutant α-synuclein and their defective clearance by autophagy plays a significant role in causing Parkinson’s disease,” Zhuang said. “Our model ties together these proposed disease-causing pathways and genes for the first time in whole animals.”

While their model mimics many important aspects of Parkinson’s, Zhuang cautions that it is unlikely that any animal model will recapitulate every aspect of the disease. However, these initial findings open up many new avenues in Parkinson’s disease research. The ability to control the mutant protein’s effects provides a powerful system to screen for therapeutics and drugs that can help patients in various stages of Parkinson’s.  It also provides a new tool to investigate the molecular mechanisms of genes that are often associated with the disease.

“We now have a valuable new model that reveals mechanisms of pathogenesis in Parkinson’s, and will be an ideal platform for testing drugs,” Zhuang said. He has already shared the new mouse model with several collaborators and researchers in the field. All are currently sifting out the molecular mechanisms of A53T toxicity and how parkin and PINK1 functions in Parkinson’s disease.

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The study “A53T Human -Synuclein Overexpression in Transgenic Mice Induces Pervasive Mitochondria Macroautophagy Defects Preceding Dopamine Neuron Degeneration,” was funded by the Parkinson’s Disease Foundation, the National Center for Research Resources and the National Center for Advancing Translational Sciences of the National Institutes of Health, the Michael J. Fox Foundation for Parkinson’s Research, and American Parkinson Disease Association Research Grants. Additional authors include Linan Chen, Zhiguo Xie, and Susie Turkson,

 

About Matthew Tien (2 Articles)
Matthew Tien is a graduate student in the Department of Biochemistry and Molecular Biology at the University of Chicago. He's currently a member in Sean Crosson's Lab.
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