Title

Cysteine-Rich Granulin-3 Rapidly Promotoes Amyloid-β Fibrils in Both Redox States

Document Type

Article

Publication Date

3-12-2019

Department

Chemistry and Biochemistry

Abstract

Granulins (GRNs 1–7) are cysteine-rich proteolytic products of progranulin (PGRN) that have recently been implicated in neurodegenerative diseases including frontotemporal dementia (FTD) and Alzheimer's disease (AD). Their precise mechanism in these pathologies remains uncertain, but both inflammatory and lysosomal roles have been observed for GRNs. Among the seven GRNs, GRN-3 is well characterized and is implicated within the context of FTD. However, the relationship between GRN-3 and amyloid-β (Aβ), a protein relevant in AD pathology, has not yet been explored. To gain insight into this mechanism, we investigated the effect of both oxidized and reduced GRN-3 on Aβ aggregation and found that both GRN-3 (oxidized) and rGRN-3 (reduced) bind to monomeric and oligomeric Aβ42 to promote rapid fibril formation with subtle rate differences. As low molecular weight oligomers of Aβ are well-established neurotoxins, rapid promotion of fibrils by GRN-3 mitigates Aβ42-induced cellular apoptosis. These data provide valuable insights in understanding GRN-3's ability to modulate Aβ-induced toxicity under redox control and presents a new perspective toward AD pathology. These results also prompt further investigation into the role(s) of other GRNs in AD pathogenesis.

Publication Title

Biochemical Journal

Volume

476

Issue

5

First Page

859

Last Page

873

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