Antisynuclein Monoclonal Antibody Reverses Parkinson's Disease Symptoms in Culture and Mouse Models

The development of Parkinson's disease in a mouse model was blocked by treatment with monoclonal antibodies directed at alpha-synuclein (alpha-syn), the main protein component of the Lewy bodies and Lewy neurites that characterize the disease.

A Lewy body is composed of the protein alpha-synuclein associated with other proteins, such as ubiquitin, neurofilament protein, and alpha B crystalline. Similar to Lewy bodies, Lewy neurites are proteinaceous formations found in neurons of the diseased brain, comprising abnormal alpha-syn filaments and granular material. Like Lewy bodies, Lewy neurites are a feature of alpha-synucleinopathies such as dementia with Lewy bodies, Parkinson's disease, and multiple system atrophy. They are also found in the CA2-3 region of the hippocampus in Alzheimer's disease.

Investigators at the University of Pennsylvania (Philadelphia, USA) worked with culture and mouse models of Parkinson's disease that they had established during prior studies. Using these model systems they had found that synthetic preformed alpha-syn fibrils recruited endogenous alpha-syn and induced Lewy body/Lewy neurite pathology in neuron cultures and test animals, thereby implicating propagation and cell-to-cell transmission of pathological alpha-syn as mechanisms for the progressive spread of Lewy bodies and Lewy neurites.

In the current study they introduced the anti-alpha-syn monoclonal antibody Syn303 into the model systems. They reported in the June 12, 2014, online edition of the journal Cell Reports that alpha-syn monoclonal antibodies reduced alpha-syn preformed fibrils-induced Lewy body/Lewy neurite formation and rescued synapse and neuron loss in primary neuronal cultures by preventing both uptake of the preformed fibrils and subsequent cell-to-cell transmission of the disease pathology. Moreover, intraperitoneal (i.p.) administration of the Syn303 antibody into mice injected with alpha-syn preformed fibrils reduced Lewy body/Lewy neurite pathology, ameliorated neuron loss, and improved motor impairments.

"Once we created these models, the first thing that came to mind is immunotherapy," said senior author Dr. Virginia M.Y Lee, professor of pathology and laboratory medicine at the University of Pennsylvania. "If you can develop antibodies that would stop the spreading, you may have a way to at least retard the progression of Parkinson's disease. In animal models the question we want to ask is, can we reduce the pathology and also rescue cell loss to improve the behavioral deficits? But there are some limitations to experiments in live mice since it is difficult to directly study the mechanism of how it works. To do that, we went back to the cell culture model to ask whether or not the antibody basically prevents the uptake of misfolded alpha-syn. The cell culture experiments showed that MAbs prevented the uptake of misfolded alpha-syn fibrils by neurons and sharply reduced the recruitment of natural alpha-syn into new Lewy body aggregates."

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