The role of UNC5C in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease in adults characterized by the deposition of extracellular plaques of β-amyloid protein (Aβ), intracellular neurofibrillary tangles (NFTs), synaptic loss and neuronal apoptosis. AD has a strong and complex genetic component that involving into multiple genes. With recent advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS) technology, UNC5C was identified to have association with AD. Emerging studies on cell and animal models identified that aberrant UNC5C may contribute to AD by activating death-associated protein kinase 1 (DAPK1) which is a new component involved in AD pathogenesis with an extensive involvement in aberrant tau, Aβ and neuronal apoptosis/autophagy. In this review, we briefly summarize the biochemical properties, genetics, epigenetics, and the speculative role of UNC5C in AD. We hope our review would bring comprehensive understandings of AD pathogenesis and provide new therapeutic targets for AD.

[1]  Brian J Cummings,et al.  Immunohistochemical evidence for apoptosis in Alzheimer's disease. , 1994, Neuroreport.

[2]  J. Mandell,et al.  Microtubule-associated proteins, phosphorylation gradients, and the establishment of neuronal polarity. , 1996, Perspectives on developmental neurobiology.

[3]  S. Takeda,et al.  G Protein-Mediated Neuronal DNA Fragmentation Induced by Familial Alzheimer's Disease-Associated Mutants of APP , 1996, Science.

[4]  M. Masu,et al.  Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors , 1997, Nature.

[5]  S. Ackerman,et al.  Cloning and mapping of the UNC5C gene to human chromosome 4q21-q23. , 1998, Genomics.

[6]  D. Bredesen,et al.  The RET proto‐oncogene induces apoptosis: a novel mechanism for Hirschsprung disease , 2000, The EMBO journal.

[7]  F. Llambi,et al.  Netrin‐1 acts as a survival factor via its receptors UNC5H and DCC , 2001, The EMBO journal.

[8]  P. Mehlen,et al.  Inhibition of Neuroepithelial Patched-Induced Apoptosis by Sonic Hedgehog , 2003, Science.

[9]  Ken Watanabe,et al.  UNC5H1 Induces Apoptosis via Its Juxtamembrane Region through an Interaction with NRAGE* , 2003, The Journal of Biological Chemistry.

[10]  Giovanni Romeo,et al.  The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Johnson,et al.  Tau phosphorylation in neuronal cell function and dysfunction , 2004, Journal of Cell Science.

[12]  I. Nishimoto,et al.  Transforming Growth Factor (cid:2) 2 Is a Neuronal Death-Inducing Ligand for Amyloid- (cid:2) Precursor Protein , 2005 .

[13]  Taylor J. Maxwell,et al.  DAPK1 variants are associated with Alzheimer's disease and allele-specific expression. , 2006, Human molecular genetics.

[14]  N. Matsubara,et al.  Epigenetic and genetic alterations in Netrin-1 receptors UNC5C and DCC in human colon cancer. , 2007, Gastroenterology.

[15]  E. Bruyneel,et al.  Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis , 2007, Oncogene.

[16]  A. Kimchi,et al.  DAP kinase regulates JNK signaling by binding and activating protein kinase D under oxidative stress , 2007, Cell Death and Differentiation.

[17]  P. Mehlen,et al.  Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B , 2008, Nature Cell Biology.

[18]  M. Wilkinson,et al.  Epigenetic regulation and downstream targets of the Rhox5 homeobox gene. , 2008, International journal of andrology.

[19]  D. Bredesen,et al.  Netrin-1 interacts with amyloid precursor protein and regulates amyloid-β production , 2009, Cell Death and Differentiation.

[20]  M. Hoshino,et al.  Dissecting the Factors Involved in the Locomotion Mode of Neuronal Migration in the Developing Cerebral Cortex* , 2009, The Journal of Biological Chemistry.

[21]  I. Bejarano,et al.  Caspase-3 and -9 are activated in human myeloid HL-60 cells by calcium signal , 2009, Molecular and Cellular Biochemistry.

[22]  P. Mehlen,et al.  Netrin-1 and its dependence receptors as original targets for cancer therapy , 2010, Current opinion in oncology.

[23]  P. Shannon,et al.  Exome sequencing identifies the cause of a Mendelian disorder , 2009, Nature Genetics.

[24]  Jin-Tai Yu,et al.  Association of DAPK1 genetic variations with Alzheimer's disease in Han Chinese , 2011, Brain Research.

[25]  P. Wong,et al.  Amyloid precursor protein processing and Alzheimer's disease. , 2011, Annual review of neuroscience.

[26]  P. Bosco,et al.  APOE and Alzheimer disease: a major gene with semi-dominant inheritance , 2011, Molecular Psychiatry.

[27]  S. Ackerman,et al.  The UNC5C Netrin Receptor Regulates Dorsal Guidance of Mouse Hindbrain Axons , 2011, The Journal of Neuroscience.

[28]  M. Barcikowska,et al.  Identification of a late onset Alzheimer's disease candidate risk variant at 9q21.33 in Polish patients. , 2012, Journal of Alzheimer's disease : JAD.

[29]  Y. Hashimoto,et al.  MOCA is an integrator of the neuronal death signals that are activated by familial Alzheimer's disease-related mutants of amyloid β precursor protein and presenilins. , 2012, The Biochemical journal.

[30]  H. Nemoto,et al.  Methylation of the HACE1 gene is frequently detected in hepatocellular carcinoma. , 2012, Hepato-gastroenterology.

[31]  Jingxia Gao,et al.  Expression of unc5 family genes in zebrafish brain during embryonic development. , 2013, Gene expression patterns : GEP.

[32]  Y. Oh,et al.  Netrin-1 protects hypoxia-induced mitochondrial apoptosis through HSP27 expression via DCC- and integrin α6β4-dependent Akt, GSK-3β, and HSF-1 in mesenchymal stem cells , 2013, Cell Death and Disease.

[33]  Y. Hashimoto,et al.  A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity , 2014, Journal of neurochemistry.

[34]  S. Küry,et al.  Evaluation of the colorectal cancer risk conferred by rare UNC5C alleles. , 2014, World journal of gastroenterology.

[35]  H. Wood Alzheimer disease: AD-susceptible brain regions exhibit altered DNA methylation , 2014, Nature Reviews Neurology.

[36]  F. Terro,et al.  Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice , 2014, Journal of Neuroinflammation.

[37]  A. Kimchi,et al.  Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function , 2014, Cell Death and Disease.

[38]  J. Hardy,et al.  Apolipoprotein E in Alzheimer's disease: an update. , 2014, Annual review of neuroscience.

[39]  J. Haines,et al.  A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death , 2014, Nature Medicine.

[40]  B. Tang,et al.  Investigation of TREM2, PLD3, and UNC5C variants in patients with Alzheimer's disease from mainland China , 2014, Neurobiology of Aging.

[41]  N. Grishin,et al.  An ancient autoproteolytic domain found in GAIN, ZU5 and Nucleoporin98. , 2014, Journal of molecular biology.

[42]  E. Palmesino,et al.  Synergistic integration of Netrin and ephrin axon guidance signals by spinal motor neurons , 2015, eLife.

[43]  Xiao Zhen Zhou,et al.  Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease. , 2015, Biochimica et biophysica acta.

[44]  R. Wilson,et al.  Alzheimer's disease: rare variants with large effect sizes. , 2015, Current opinion in genetics & development.

[45]  L. Farrer Expanding the genomic roadmap of Alzheimer's disease , 2015, The Lancet Neurology.

[46]  Alzheimer's Disease Neuroimaging Initiative,et al.  The Impact of UNC5C Genetic Variations on Neuroimaging in Alzheimer’s Disease , 2016, Molecular Neurobiology.

[47]  Y. Sugimoto,et al.  Molecular Effects of Polymorphism in the 3’UTR of Unc-5 homolog C Associated with Conception Rate in Holsteins , 2015, PloS one.

[48]  [GENETIC AND EPIGENETIC DETERMINANTS OF ALZHEIMER'S DISEASE]. , 2015, Advances in gerontology = Uspekhi gerontologii.

[49]  O. Korvatska,et al.  R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. , 2015, JAMA neurology.

[50]  Michel Goedert,et al.  Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein , 2015, Science.

[51]  The Role of MAPT in Neurodegenerative Diseases: Genetics, Mechanisms and Therapy , 2016, Molecular Neurobiology.

[52]  The Role of Reelin Signaling in Alzheimer’s Disease , 2016, Molecular Neurobiology.

[53]  J. Sanchez-Mut,et al.  Epigenetic Alterations in Alzheimer’s Disease , 2015, Front. Behav. Neurosci..

[54]  Y. Kiriyama,et al.  The Function of Autophagy in Neurodegenerative Diseases , 2015, International journal of molecular sciences.

[55]  M. Tsolaki,et al.  Recent Findings in Alzheimer Disease and Nutrition Focusing on Epigenetics. , 2016, Advances in nutrition.

[56]  Fei Liu,et al.  Tau and neurodegenerative disease: the story so far , 2016, Nature Reviews Neurology.

[57]  Xiaolong Wang,et al.  The Role of 99mTc-Annexin V Apoptosis Scintigraphy in Visualizing Early Stage Glucocorticoid-Induced Femoral Head Osteonecrosis in the Rabbit , 2016, BioMed research international.

[58]  W. Klein,et al.  Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology , 2016, Acta Neuropathologica.

[59]  M. Urioste,et al.  Scarce evidence of the causal role of germline mutations in UNC5C in hereditary colorectal cancer and polyposis , 2016, Scientific Reports.

[60]  Y. Hashimoto,et al.  An Alzheimer Disease-linked Rare Mutation Potentiates Netrin Receptor Uncoordinated-5C-induced Signaling That Merges with Amyloid β Precursor Protein Signaling* , 2016, The Journal of Biological Chemistry.

[61]  Palaniyandi Ravanan,et al.  Death Associated Protein Kinase 1 (DAPK1): A Regulator of Apoptosis and Autophagy , 2016, Front. Mol. Neurosci..

[62]  L. Cantley,et al.  Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death , 2016, Cell Death and Differentiation.

[63]  J. Attems,et al.  Interactions of pathological proteins in neurodegenerative diseases , 2017, Acta Neuropathologica.

[64]  L. Saso,et al.  Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer’s disease and Parkinson’s disease , 2017, Drug design, development and therapy.

[65]  Olivier Rouaud,et al.  APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases , 2017, PLoS medicine.

[66]  M. Korte,et al.  Not just amyloid: physiological functions of the amyloid precursor protein family , 2017, Nature Reviews Neuroscience.

[67]  T. Hartmann,et al.  APP Function and Lipids: A Bidirectional Link , 2017, Front. Mol. Neurosci..

[68]  J. Herz,et al.  ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease , 2017, Trends in Endocrinology & Metabolism.

[69]  L. Megeney,et al.  Evolution of caspase-mediated cell death and differentiation: twins separated at birth , 2017, Cell Death and Differentiation.

[70]  M. Mendez Early-Onset Alzheimer Disease. , 2017, Neurologic clinics.

[71]  Jie Wu,et al.  Methylation of the UNC5C gene and its protein expression in colorectal cancer , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[72]  Toshitaka Nagao,et al.  Plaque formation and the intraneuronal accumulation of β‐amyloid in Alzheimer's disease , 2017, Pathology international.