Parkinson’s Researchers May Finally Have a Mouse Model to Test New Treatments

Margarida Azevedo, MSc avatar

by Margarida Azevedo, MSc |

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Better model for Parkinson's disease

An animal model capable ofĀ reproducing the formation of Ī±-synuclein fibrils and, consequently, Lewy bodies ā€” the major pathological hallmark of Parkinsonā€™s disease ā€” has finally been developed. Researchers reporting this achievement, in a study titledĀ ā€œInduction of de novo Ī±-synuclein fibrillization in a novel neuronal model for Parkinson’s diseaseā€ and published inĀ PNAS,Ā expect their model to considerably aidĀ Parkinson’s research and treatment.

Ī±-synuclein, an abundant protein in the healthy human brain, is the major constituent of Lewy bodies. Overproduction and aggregation of Ī±-synuclein leads to fibrils that form Lewy bodies, the protein clump inclusions that appear within neurons and causeĀ neuronal and synaptic damage. Researchers have long tried to develop animal models able toĀ reproduce this pathology, both to better understand Parkinson’s disease (PD) and betterĀ screen potential therapeutic drugs. But until now,Ā the overproduction of human Ī±-synuclein in mice failed to result in the characteristic fibrils or Lewy bodies found in human PD brains, hindering PDĀ modeling, research, and drug development.

Researchers wonderedĀ if theĀ inability to form pathological structures was due to interactions between human and mouse forms ofĀ Ī±-synuclein. These animalsĀ produce three types of Ī±-synuclein, allĀ similar to the human protein. To observe the effects, the teamĀ investigated what would happen to human Ī±-synuclein when it was produced in mice neurons genetically engineered not to produce one or all forms of their own Ī±-synuclein homologues.

Results revealedĀ that mouse protein homologues did indeed interfere with fibril and Lewy body formation. Mice neurons engineered not to produce mouse Ī±-synuclein successfully formed Lewy body-like clumps. Mouse homologues interacted with early intermediates of human Ī±-synuclein aggregation, the researchers determined, preventing the protein’sĀ development into pathological Lewy bodies and their spread throughout the brain.

This important discovery shows why it was so difficultĀ to model PD in mice, and opensĀ the way toĀ engineered mice and neuronal cultures crucial for medical and drug research. “We now have a very well-characterized model that offers a powerful tool for rapid screening of molecular pathways involved in Parkinson’s disease,” Mohamed-Bilal Fares, the study lead author and a PhD student, said in a news release. “But because it can also allow us to understand how human alpha-synuclein forms fibrils inside neurons and how that contributes to the progression of the disease, we can develop better drugs and intervention strategies to prevent this disease.”