RESUMO
Keratin 9 was recently identified as an important component of a biomarker panel which demonstrated a high diagnostic accuracy (87%) for Alzheimer's disease (AD). Understanding how a protein which is predominantly expressed in palmoplantar epidermis is implicated in AD may shed new light on the mechanisms underlying the disease. Here we use immunoassays to examine blood plasma expression patterns of Keratin 9 and its relationship to other AD-associated proteins. We correlate this with the use of an in silico analysis tool VisANT to elucidate possible pathways through which the involvement of Keratin 9 may take place. We identify possible links with Dickkopf-1, a negative regulator of the wnt pathway, and propose that the abnormal expression of Keratin 9 in AD blood and cerebrospinal fluid may be a result of blood brain barrier dysregulation and disruption of the ubiquitin proteasome system. Our findings suggest that dysregulated Keratin 9 expression is a consequence of AD pathology but, as it interacts with a broad range of proteins, it may have other, as yet uncharacterized, downstream effects which could contribute to AD onset and progression.
Assuntos
Doença de Alzheimer/metabolismo , Biomarcadores/análise , Queratina-9/análise , Transdução de Sinais , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Estudos de Coortes , Biologia Computacional/métodos , Feminino , Humanos , Imunoensaio/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Queratina-9/metabolismo , Queratina-9/fisiologia , Masculino , Fragmentos de Peptídeos/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Mapas de Interação de Proteínas , Proteínas tau/metabolismoRESUMO
Keratin 9 (K9) is a type I intermediate filament protein whose expression is confined to the suprabasal layers of the palmoplantar epidermis. Although mutations in the K9 gene are known to cause epidermolytic palmoplantar keratoderma, a rare dominant-negative skin disorder, its functional significance is poorly understood. To gain insight into the physical requirement and importance of K9, we generated K9-deficient (Krt9(-/-)) mice. Here, we report that adult Krt9(-/-)mice develop calluses marked by hyperpigmentation that are exclusively localized to the stress-bearing footpads. Histological, immunohistochemical, and immunoblot analyses of these regions revealed hyperproliferation, impaired terminal differentiation, and abnormal expression of keratins K5, K14, and K2. Furthermore, the absence of K9 induces the stress-activated keratins K6 and K16. Importantly, mice heterozygous for the K9-null allele (Krt9(+/-)) show neither an overt nor histological phenotype, demonstrating that one Krt9 allele is sufficient for the developing normal palmoplantar epidermis. Together, our data demonstrate that complete ablation of K9 is not tolerable in vivo and that K9 is required for terminal differentiation and maintaining the mechanical integrity of palmoplantar epidermis.
Assuntos
Epiderme/fisiologia , Queratina-9/genética , Queratina-9/fisiologia , Ceratodermia Palmar e Plantar Epidermolítica/genética , Fatores Etários , Animais , Diferenciação Celular/fisiologia , Proliferação de Células , Citoesqueleto/patologia , Modelos Animais de Doenças , Epiderme/patologia , Hiperpigmentação/genética , Hiperpigmentação/patologia , Ceratodermia Palmar e Plantar Epidermolítica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Interferente Pequeno/genéticaRESUMO
In this article we reviewed the current researches on the molecular basis of epidermolytic palmoplantar keratoderma (EPPK) and the structure and function of the keratins with mutations that can cause inherited keratin disorders. Also summarized are seventeen mutations of keratin 9 in EPPK in different ethnic populations.
