Agrin Binds α-synuclein and Modulates α-synuclein Fibrillation
Agrin, Heparan Sulfate Proteoglycan, Parkinson’s Disease, Protein Conformational Disorders, α-synuclein
Digital Object Identifier (DOI)
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 β-amyloid (Aβ) 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 α-synuclein fibrils being enhanced by sulfated macromolecules. In the studies reported here, we show that agrin binds to α-synuclein in a heparan sulfate-dependent (HS-dependent) manner, induces conformational changes in this protein characterized by β-sheet structure, and enhances insolubility of α-synuclein. We also show that agrin accelerates the formation of protofibrils by α-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 α-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.
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Citation / Publisher Attribution
Glycobiology, v. 15, issue 12, p. 1320-1331
Scholar Commons Citation
Ni, I-Hsun; Uversky, Vladimir N.; Munishkina, Larissa A.; Fink, Anthony L.; Halfter, Willi; and Cole, Gregory J., "Agrin Binds α-synuclein and Modulates α-synuclein Fibrillation" (2005). Molecular Medicine Faculty Publications. 750.