Low-density lipoprotein receptor-related protein 4

Low-density lipoprotein receptor-related protein 4 (LRP4) is a 1905-amino-acid cell surface receptor that mediates multiple signaling pathways. It functions as a key facilitator of sclerostin (SOST)-dependent inhibition of Wnt signaling and plays an essential role in neuromuscular junction formation by directly binding agrin and recruiting it to the MUSK signaling complex, thereby promoting acetylcholine receptor clustering. Additionally, LRP4 may function as an endocytic receptor for ligand internalization and degradation (UniProt: O75096).

LRP4 is expressed in bone and neuromuscular tissues. Genetic variations in LRP4 are associated with Mendelian disorders including Cenani-Lenz syndactyly syndrome, sclerosteosis 2, and congenital myasthenic syndrome 17 (UniProt: O75096). These associations highlight its critical roles in skeletal development and synaptic function.

LRP4 is upregulated in post-mortem Alzheimer's disease brain tissue compared to age-matched controls, with a mean log2 fold-change of 0.56 across subcellular fractions (Chaparral AD proteomics). This upregulation in human AD brain suggests a potential disease-relevant role, though the specific pathobiological consequence remains to be determined.