The Neuroendocrine Protein 7B2 Suppresses the Aggregation of Neurodegenerative Disease-related Proteins*

Abstract

Background: The neuroendocrine protein 7B2 blocks the aggregation of certain secreted proteins.

Results: 7B2 co-localizes with protein aggregates in Parkinson and Alzheimer disease brains; blocks the fibrillation of Aβ _1–40, Aβ _1–42, and α-synuclein; and blocks Aβ _1–42-induced Neuro-2A cell death.

Conclusion: 7B2 inhibits the cytotoxicity of Aβ _1–42 by modulation of oligomer formation.

Significance: 7B2 is a novel anti-aggregation secretory chaperone associated with neurodegenerative disease.

Abstract

Neurodegenerative diseases such as Alzheimer (AD) and Parkinson (PD) are characterized by abnormal aggregation of misfolded β-sheet-rich proteins, including amyloid-β (Aβ)-derived peptides and tau in AD and α-synuclein in PD. Correct folding and assembly of these proteins are controlled by ubiquitously expressed molecular chaperones; however, our understanding of neuron-specific chaperones and their involvement in the pathogenesis of neurodegenerative diseases is limited. We here describe novel chaperone-like functions for the secretory protein 7B2, which is widely expressed in neuronal and endocrine tissues. In in vitro experiments, 7B2 efficiently prevented fibrillation and formation of Aβ _1–42, Aβ _1–40, and α-synuclein aggregates at a molar ratio of 1:10. In cell culture experiments, inclusion of recombinant 7B2, either in the medium of Neuro-2A cells or intracellularly via adenoviral 7B2 overexpression, blocked the neurocytotoxic effect of Aβ _1–42 and significantly increased cell viability. Conversely, knockdown of 7B2 by RNAi increased Aβ _1–42-induced cytotoxicity. In the brains of APP/PSEN1 mice, a model of AD amyloidosis, immunoreactive 7B2 co-localized with aggregation-prone proteins and their respective aggregates. Furthermore, in the hippocampus and substantia nigra of human AD- and PD-affected brains, 7B2 was highly co-localized with Aβ plaques and α-synuclein deposits, strongly suggesting physiological association. Our data provide insight into novel functions of 7B2 and establish this neural protein as an anti-aggregation chaperone associated with neurodegenerative disease.