Protein Found Blocks Transmission of Cytotoxic Fibrils in Parkinson's Disease Model

Neurodegenerative disease researchers have identified a protein that promotes the spread of toxic alpha-synuclein complexes in the brains of mice serving as a model system for human Parkinson's disease (PD).

In the brains of PD patients, pathologic alpha-synuclein seems to spread from cell to cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The underlying mechanisms and molecular entities responsible for the transmission of pathologic alpha-synuclein from cell to cell are not known.

Investigators at Johns Hopkins University (Baltimore, MD, USA) studied the spread of pathologic alpha-synuclein complexes in cell cultures and in a mouse PD model. They used recombinant alpha-synuclein preformed fibril complexes (PFF) as a model system with which to study the transmission of misfolded alpha-synuclein from neuron to neuron.

The investigators screened a library of genes that encode transmembrane proteins to identify alpha-synuclein-biotin PFF–binding candidates via detection with streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bound alpha-synuclein PFF and included lymphocyte-activation gene 3 (LAG3), neurexin 1beta, and amyloid beta precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for alpha-synuclein PFF over the alpha-synuclein monomer.

Results published in the September 30, 2016, online edition of the journal Science revealed that LAG3 was specific for alpha-synuclein PFF. The internalization of alpha-synuclein PFF involved LAG3, since deletion of LAG3 reduced the endocytosis of alpha-synuclein PFF. Neuron-to-neuron transmission of pathologic alpha-synuclein and the accompanying pathology and neurotoxicity was substantially attenuated by deletion of LAG3 or by antibodies to LAG3.

The lack of LAG3 substantially delayed alpha-synuclein PFF–induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo. The identification of LAG3 as a receptor that binds alpha-synuclein PFF provides a target for developing therapeutics designed to slow the progression of PD.

“Other labs showed alpha-synuclein might spread from cell to cell,” said senior author Dr. Ted Dawson, director of the institute for cell engineering at Johns Hopkins University. “Typical mice develop Parkinson’s-like symptoms soon after they are injected [with alpha-synuclein PFF], and within six months, half of their dopamine-making neurons die, but mice without LAG3 were almost completely protected from these effects. Antibodies that blocked LAG3 had similar protective effects in cultured neurons.”

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