Agrin binds -synuclein and modulates -synuclein fibrillation

Recent studies have begun to investigate the role of agrin in brain and suggest that agrin’s function likely extends beyond that of a synaptogenic protein. Particularly, it has been shown that agrin is associated with the pathological lesions of Alzheimer’s disease (AD) and may contribute to the formation of -amyloid (A ) plaques in AD. We have extended the analysis of agrin’s function in neurodegenerative diseases to investigate its role in Parkinson’s disease (PD). α-Synuclein is a critical molecular determinant in familial and sporadic PD, with the formation of -synuclein fibrils being enhanced by sulfated macromolecules. In the studies reported here, we show that agrin binds to synuclein in a heparan sulfate-dependent (HS-dependent) manner, induces conformational changes in this protein characterized by -sheet structure, and enhances insolubility of -synuclein. We also show that agrin accelerates the formation of protofibrils by -synuclein and decreases the half-time of fibril formation. The association of agrin with PD lesions was also explored in PD human brain, and these studies shown that agrin colocalizes with -synuclein in neuronal Lewy bodies in the substantia nigra of PD brain. These studies indicate that agrin is capable of accelerating the formation of insoluble protein fibrils in a second common neurodegenerative disease. These findings may indicate shared molecular mechanisms leading to the pathophysiology in these two neurodegenerative disorders.