Heparan Sulfate Dependent Mechanisms of Amyloidosis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
A common theme in amyloid disorders is the deposition of disease-specific protein aggregates in tissues. Amyloid proteins bind to heparan sulfate (HS), a sulfated glycosaminoglycan, and HS has been found to promote the aggregation process. The present work relates to HS mediated mechanisms of amyloidosis, particularly transthyretin (TTR) amyloidosis, AA-amyloidosis and Alzheimer’s disease (AD).
TTR is a transport protein present in the blood and cerebrospinal fluid, which under unclear circumstances can deposit as amyloid in the myocardium of elderly individuals. Examination of cardiac tissue from a 70 year old patient with reported cardiomyopathy reveald co-deposition of TTR amyloid and HS. Studies revealed that HS promotes TTR fibrillization through interaction with a basic motif in the protein. Empolyment of a cell model demonstrated that cell surface HS mediates internalization of TTR, an effect likely facilitated by HS-binding to the basic motif on TTR. Collectively, HS-TTR interactions at the cell surface may have dual outcomes, resulting in either fibrillization or internalization, respectively.
During inflammatory conditions, serum amyloid A (SAA), an acute-phase protein associated with the high-density lipoprotein (HDL), can assemble into insoluble amyloid fibrils, causing AA-amyloidosis. We found that HS structures exceeding 12-14 sugar units in length separates SAA from HDL and induces subsequent aggregation of the polypeptide. Our result proposes a novel role for HS in AA-amyloidosis in which a critical length of HS is required for separation of SAA from HDL.
Late-onset AD patients show reduced ability to clear cerebral amyloid-β (Aβ) aggregates, a pathological hallmark of the disease. Althought the pathway of Aβ clearance is still unclear, several cell-surface receptors are implicated in Aβ internalization. We found that ApoE facilitated Aβ uptake through interactions with HS-proteoglycans and low-density lipoprotein receptor-related protein 1. The ApoE interaction with Aβ likely promotes Aβ clearance in the brain, but, if unbalanced, may contribute to the pathology of AD.
These findings are in accord with the concept of HS as a promoter of amyloid protein aggregation, but also point to more complex relationship.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 41 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 740
Amyloidosis, Heparan sulfate, Transthyretin, Serum amyloid A, Amyloid-beta, lipoproteins
Biochemistry and Molecular Biology
Research subject Medical Biochemistry
IdentifiersURN: urn:nbn:se:uu:diva-168309ISBN: 978-91-554-8272-5OAI: oai:DiVA.org:uu-168309DiVA: diva2:492898
2012-03-23, B42, BMC, Husargatan 3, Uppsala, Uppsala, 09:15 (English)
Merlini, Giampaolo, Professor
Li, Jin-ping, DrLindahl, Ulf, Professor
List of papers