MGluR4-Npdc1 complex mediates α-synuclein fibril-induced neurodegeneration.

ABSTRACT: 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 o

SUBMITTER: Perez-Canamas A 

PROVIDER: S-EPMC12330738 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature