title: 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.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Helwig
authors.forename: Akina
authors.initials: A
authors.lastname: Hoshino
authors.forename: Casey
authors.initials: C
authors.lastname: Berridge
authors.forename: Sang-Nam
authors.initials: SN
authors.lastname: Lee
authors.forename: Nikolai
authors.initials: N
authors.lastname: Lorenzen
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Otzen
authors.forename: Jason L
authors.initials: JL
authors.lastname: Eriksen
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D051859:Neuroendocrine Secretory Protein 7B2 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051859:Neuroendocrine Secretory Protein 7B2; C497678:SCG5 protein, human; D051844:alpha-Synuclein