mGluR4-Npdc1 complex mediates α-synuclein fibril-induced neurodegeneration

Fibrils of misfolded α-synuclein (α-syn) accumulate in Parkinson's disease and other synucleinopathies, spreading between cells to template further misfolding and drive neurodegeneration. α-syn fibril entry into healthy neurons is recognized as a key step in the disease process but remains ill-defined mechanistically. Here, we comprehensively assessed the membrane proteome for binding of α-syn fibrils. Expression cloning identified mGluR4 and Npdc1 as plasma membrane proteins expressed by substantia nigra neurons capable of supporting high affinity α-syn fibril binding. Moreover, mGluR4 and Npdc1 cellular signaling functions were titrated by the presence of extracellular fibrillary α-syn. While striatal α-syn fibril injection led to nigral dopamine neuron loss in wild type mice, deletion of either Grm4 or Npdc1 provided protection of dopamine neurons. We observed mGluR4 and Npdc1 to form a complex that regulates mGluR4 signaling. Cultured neurons lacking both Grm4 and Npdc1 fail to bind α-syn fibrils, to accumulate phosphorylated α-syn and to lose synapses. Transheterozygous Grm4, Npdc1 mice showed protection from nigral neuron loss after striatal α-syn injection, demonstrating genetic interaction between the two binding proteins. On a transgenic α-syn A53T background, double Grm4, Npdc1 heterozygosity robustly increased mouse survival, motor function and spinal motoneuron number. Thus, a cell surface mGluR4-Npdc1 complex participates in α-syn neurodegeneration.