Agrin binds alpha-synuclein and modulates alpha-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 beta-amyloid (Abeta) plaques in AD. We have extended the analysis of agrin's function in neurodegenerative diseases to investigate its role in Parkinson's disease (PD). Alpha-synuclein is a critical molecular determinant in familial and sporadic PD, with the formation of alpha-synuclein fibrils being enhanced by sulfated macromolecules. In the studies reported here, we show that agrin binds to alpha-synuclein in a heparan sulfate-dependent (HS-dependent) manner, induces conformational changes in this protein characterized by beta-sheet structure, and enhances insolubility of alpha-synuclein. We also show that agrin accelerates the formation of protofibrils by alpha-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 alpha-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.
Liu
I-Hsuan
IH
Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA.
Uversky
Vladimir N
VN
Munishkina
Larissa A
LA
Fink
Anthony L
AL
Halfter
Willi
W
Cole
Gregory J
GJ
D018171:Agrin / Q000737:chemistry* / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002645:Chickens; D002942:Circular Dichroism; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D011328:Prions / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D012995:Solubility; D013378:Substantia Nigra / Q000378:metabolism; D051843:Synucleins / Q000737:chemistry; D013997:Time Factors; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism
D018171:Agrin; D000911:Antibodies, Monoclonal; D006497:Heparan Sulfate; D011328:Prions; D011994:Recombinant Proteins; D051843:Synucleins; D051844:alpha-Synuclein