The neuroendocrine protein 7B2 suppresses the aggregation of neurodegenerative disease-related proteins.

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.

• Authors: Michael Helwig, Akina Hoshino, Casey Berridge, Sang-Nam Lee, Nikolai Lorenzen, Daniel E Otzen, Jason L Eriksen, Iris Lindberg
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 2 Pg. 1114-24 (Jan 11 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23172224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Neuroendocrine Secretory Protein 7B2
• SCG5 protein, human
• alpha-Synuclein

Topics

• Aged
• Amino Acid Sequence
• Amyloid beta-Peptides (antagonists & inhibitors, metabolism)
• Animals
• Cell Death (physiology)
• Female
• Hippocampus (metabolism)
• Humans
• Immunohistochemistry
• Mice
• Mice, Transgenic
• Microscopy, Electron, Transmission
• Molecular Sequence Data
• Neurodegenerative Diseases (metabolism)
• Neuroendocrine Secretory Protein 7B2 (chemistry, metabolism, physiology)
• Substantia Nigra (metabolism)
• alpha-Synuclein (antagonists & inhibitors, metabolism)