Researchers identified a receptor on neurons that lets the toxic protein of Parkinson's disease into the cell: without it, brain-wide spread dropped by 70–99% in mice, and a human-tested antibody blocked the same gateway
Researchers identified a receptor on neurons that lets the toxic protein of Parkinson's disease into the cell: without it, brain-wide spread dropped by 70–99% in mice, and a human-tested antibody blocked the same gateway
FcγRIIb (also known as CD32b) is a receptor that normally belongs to a family of molecules restraining immune cells. In a paper published September 25 in Acta Neuropathologica, a team from the University of Southampton showed that the same receptor is required by neurons to take up fibrils, thin filaments of aggregated alpha-synuclein, a protein whose cell-to-cell spread drives Parkinson's disease. In mice lacking the receptor, the dopaminergic neurons that die in this disease remained intact; blocking antibodies likewise sharply reduced accumulation of the protein itself.
Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's, affecting nearly 12 million people. In Parkinson's, the protein alpha-synuclein aggregates into fibrils and spreads from neuron to neuron like an infectious prion, causing healthy copies of the protein to misfold. This chain reaction propagates through connected brain regions and kills the dopaminergic neurons of the substantia nigra, the cells whose loss causes tremor and rigidity. The gateway through which fibrils enter a healthy cell and set off this process had remained unknown.
The researchers injected synthetic alpha-synuclein fibrils into the brains of mice and compared wild-type animals with mice lacking the gene for this receptor. In receptor-knockout mice, spread of the pathological protein was reduced by 70% in the substantia nigra and by nearly 99% in the frontal and motor cortex at three months. In neuronal cultures free of immune cells, removing the receptor reduced formation of pathological protein by 88%. The receptor is needed by the neuron itself to take up the fibril.
Receptor-knockout mice were protected across every measure: their dopaminergic neurons and the density of neuronal projections were preserved, and in tests of motor function and exploratory behavior they were indistinguishable from healthy controls.
The gene cannot be knocked out in humans, so the team tested blocking antibodies. Mice carrying the human receptor received one of two antibody variants (with either a functional or a disabled Fc tail) together with the fibrils. Both reduced accumulation of pathological protein by 90%, regardless of whether the antibody's Fc tail was functional. The protection appears to come from physically blocking the site where the fibril docks onto the receptor.
BI-1206 and BI-1607 have already been tested in humans for other diseases: the charity Cancer Research UK ran a phase I/II trial of BI-1206 in B-cell lymphoma, and BI-1607 completed a phase I trial in HER2-positive tumors.
The idea builds on an earlier observation: in cell culture, fibrils were already shown to bind FcγRIIb, the only inhibitory Fc receptor conserved across species, making it a convenient target for translating results from mice to humans. Testing this connection in a living brain was made possible by a 2018 grant the Southampton team received from the Michael J. Fox Foundation, the world's largest private Parkinson's research program, founded by the actor after his diagnosis at age 29.
Prasinezumab (Roche) and cinpanemab (Biogen) targeted alpha-synuclein itself and failed to slow disease progression in phase II trials; cinpanemab was discontinued in 2021. The Southampton team targeted a different point of intervention: the receptor that serves as the gateway through which fibrils enter the cell, a gateway for which a partially human-tested antibody already exists.