title: Overexpression of Protocadherin-10 in Transthyretin-Related Familial Amyloidotic Polyneuropathy.
abstract: Overwhelming data suggest that oncogenic and neurodegenerative pathways share several altered cellular responses to insults such as oxidative stress, extracellular matrix remodeling, inflammation, or cell dyscommunication. Protocadherin-10 (Pcdh10) is an adhesion molecule found to protect against tumorigenesis and essential for axonal elongation and actin dynamics during development. Here, by using genome microarrays we identified for the first time Pcdh10 up-regulation in tissues from transgenic mouse models, cultured Schwann cells, and human samples from a familial form of peripheral neuropathy (familial amyloidotic polyneuropathy). Familial amyloidotic polyneuropathy is characterized by poor functional recovery and impaired nerve regenerative response after misfolding and deposition in the peripheral nervous system of mutant transthyretin. Not only increased transcriptional and translational Pcdh10 levels occurred in axons and Schwann cells of nerves with deposited transthyretin aggregates but the pattern also extended to associated cues of axon guidance like neuropilin-1 and F-actin. These findings suggest that Pcdh10 may influence subcellular actin cytoskeletal organization and axon-axon interactions in the course of familial amyloidotic polyneuropathy. Moreover, when preventing nonfibrillar transthyretin deposition with anakinra or transthyretin siRNA, Pcdh10 protein levels were reduced, highlighting its potential as a novel disease biomarker. Whether Pcdh10 overexpression in familial amyloidotic polyneuropathy represents a protective or deleterious response, enhancing survival or promoting cell death will need further investigation.
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, Porto, Portugal; Molecular Neurobiology Group, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Nádia P
authors.initials: NP
authors.lastname: Gonçalves
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, Porto, Portugal; Molecular Neurobiology Group, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.
authors.forename: Diana
authors.initials: D
authors.lastname: Martins
authors.affiliation: Instituto de Inovação e Investigação em Saúde (I3S), Universidade do Porto, Porto, Portugal; Molecular Neurobiology Group, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. Electronic address: mjsaraiv@ibmc.up.pt.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000032:analysis / Q000096:biosynthesis*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D011228:Prealbumin / Q000378:metabolism; D000091363:Protocadherins; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D015820:Cadherins; C438603:PCDH10 protein, human; C117277:Pcdh10 protein, mouse; D011228:Prealbumin; D000091363:Protocadherins