Abstract:
:Extracellular deposition of amyloid-beta (Aβ) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer's disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and Aβ generation. In this study, we demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aβ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aβ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aβ. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased Aβ generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Kim BM,You MH,Chen CH,Suh J,Tanzi RE,Ho Lee Tdoi
10.1093/hmg/ddw114subject
Has Abstractpub_date
2016-06-15 00:00:00pages
2498-2513issue
12eissn
0964-6906issn
1460-2083pii
ddw114journal_volume
25pub_type
杂志文章abstract::Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotid...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt460
更新日期:2014-02-01 00:00:00
abstract::Williams syndrome (WS) is a neurodevelopmental disorder caused by a 1.5-1.8 Mbp deletion on chromosome 7q11.23, affecting the copy number of 26-28 genes. Phenotypes of WS include cardiovascular problems, craniofacial dysmorphology, deficits in visual-spatial cognition and a characteristic hypersocial personality. Ther...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz176
更新日期:2019-10-15 00:00:00
abstract::Melanomas contain high frequencies of tumorigenic cells and their tumorigenic capacity resides in several distinct subpopulations within melanoma. Since their metastatic potential is linked to their ability to recruit lymphatic vessels, we aimed at identifying lymphangiogenic subpopulations by comparative in vitro ana...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds171
更新日期:2012-08-01 00:00:00
abstract::The first 17 amino acids of Huntington's disease (HD) protein, huntingtin, comprise an amphipathic alpha-helical domain that can target huntingtin to the endoplasmic reticulum (ER). N17 is phosphorylated at two serines, shown to be important for disease development in genetic mouse models, and shown to be modified by ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds554
更新日期:2013-04-01 00:00:00
abstract::Cytoglobin (CYGB) is frequently downregulated in many types of human malignancies, and its exogenous overexpression reduces proliferation of cancer cells. Despite its implied tumour suppressor (TSG) functions, its exact role in carcinogenesis remains unclear as CYGB upregulation is also associated with tumour hypoxia ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt174
更新日期:2013-08-15 00:00:00
abstract::17p13.3 microduplication syndrome is a newly identified genetic disorder characterized by duplications in the 17p13.3 chromosome locus, resulting in a variety of disorders including autism spectrum disorder (ASD). Importantly, a minimum duplication region has been defined, and this region exclusively contains the gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw270
更新日期:2016-10-15 00:00:00
abstract::Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv402
更新日期:2015-12-15 00:00:00
abstract::Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome in which affected individuals have a greatly increased predisposition to the development of haemangioblastomas of the central nervous system and retina, renal cell carcinoma and phaeochromocytoma. The VHL gene has been mapped to chromos...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.7.879
更新日期:1993-07-01 00:00:00
abstract::Fragile X Syndrome is the most common form of hereditary mental retardation. It is caused by a large expansion of the CGG trinucleotide repeat (>200 repeats) in the 5'-untranslated region (UTR) of the FMR1 gene that leads to silencing of its transcript. Individuals with CGG repeat expansions approximately between 60 a...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm186
更新日期:2007-10-01 00:00:00
abstract::Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endopla...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm217
更新日期:2007-11-01 00:00:00
abstract::Epidermolytic hyperkeratosis (EHK) is a blistering skin disease inherited as an autosomal-dominant trait. The disease is caused by genetic defects of the epidermal keratin K1 or K10, leading to an impaired tonofilament network of differentiating epidermal cells. Here, we describe for the first time a kindred with rece...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl028
更新日期:2006-04-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) are two neurodegenerative disorders characterized by the accumulation of TDP-43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FT...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv193
更新日期:2015-08-15 00:00:00
abstract::The extracellular microfibril, 10-14 nm in diameter, performs a number of functions, including serving as the scaffolding for deposition of tropoelastin to form elastic fibers. A variety of proteins compose the structure of microfibrils, the most prominent of which are the two fibrillins. Fibrillin-1 is encoded by FBN...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/4.suppl_1.1799
更新日期:1995-01-01 00:00:00
abstract::Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of N...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.24.2751
更新日期:2001-11-15 00:00:00
abstract::Rett syndrome (RTT) is an X-linked dominant disabling neurodevelopmental disorder caused by loss of function mutations in the MECP2 gene, located at Xq28, which encodes a multifunctional protein. MECP2 expression is regulated in a developmental stage and cell-type-specific manner. The need for tightly controlled MeCP2...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl099
更新日期:2006-06-01 00:00:00
abstract::Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connec...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx110
更新日期:2017-06-15 00:00:00
abstract::Mitochondrial DNA (mtDNA) depletion syndrome (MDS), an autosomal recessive condition, is characterized by variable organ involvement with decreased mtDNA copy number and activities of respiratory chain enzymes in affected tissues. MtDNA depletion has been associated with mutations in nine autosomal genes, including th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn143
更新日期:2008-08-15 00:00:00
abstract::A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from i...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/7.4.751
更新日期:1998-04-01 00:00:00
abstract::Human GM1-gangliosidosis is caused by a genetic deficiency of lysosomal acid beta-galactosidase (beta-gal). The disease manifests itself either as an infantile, juvenile or adult form and is primarily a neurological disorder with progressive brain dysfunction. A mouse model lacking a functional beta-gal gene has been ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.2.205
更新日期:1997-02-01 00:00:00
abstract::Inherited mitochondrial optic neuropathies, such as Leber's hereditary optic neuropathy (LHON) and Autosomal dominant optic atrophy (ADOA) are caused by mutant mitochondrial proteins that lead to defects in mitochondrial complex 1-driven ATP synthesis, and cause specific retinal ganglion cell (RGC) loss. Complex 1 def...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx373
更新日期:2017-12-15 00:00:00
abstract::The FKHR gene, which contains a forkhead DNA-binding motif, is fused to either PAX3 or PAX7 by the t(2;13) or t(1;13) translocation in alveolar rhabdomyosarcoma,respectively. These tumors express chimeric transcripts encoding the N-terminal portion of either PAX protein fused to the C-terminal portion of FKHR. To unde...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.12.2355
更新日期:1995-12-01 00:00:00
abstract::Mutations in SOX18, VEGFC and Vascular Endothelial Growth Factor 3 underlie the hereditary lymphatic disorders hypotrichosis-lymphedema-telangiectasia (HLT), Milroy-like lymphedema and Milroy disease, respectively. Genes responsible for hereditary lymphedema are key regulators of lymphatic vascular development in the ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt518
更新日期:2014-03-01 00:00:00
abstract::Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+/- and Tsc2+/- mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp149
更新日期:2009-06-15 00:00:00
abstract::Despite the clinical importance of human aneuploidy, we know little of the causes of mammalian non-disjunction. In part, this reflects the fact that, unlike lower organisms, segregation 'impaired' chromosomes are virtually non-existent in mammals. To address this issue, we have studied the mouse Y chromosome on the BA...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.9.963
更新日期:2001-04-15 00:00:00
abstract::To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SN...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw200
更新日期:2016-08-15 00:00:00
abstract::Type V collagen is a constituent of type I collagen-rich fibrils in many connective tissues and is a regulator of fibril diameter. In tissues, type V collagen is a heterotrimer with the molecular structure: alpha 1(V)2 alpha 2(V) or alpha 1(V) alpha 2(V) alpha 3(V). We report that genomic polymorphisms at the pro alph...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.11.1733
更新日期:1996-11-01 00:00:00
abstract::The Vesicle-associated membrane protein (VAMP)-Associated Protein B (VAPB) is the causative gene of amyotrophic lateral sclerosis 8 (ALS8) in humans. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective death of motor neurons leading to spasticity, muscle atrophy an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt118
更新日期:2013-07-01 00:00:00
abstract::DNA methylation (DNAm) has been linked to changes in chromatin structure, gene expression and disease. The DNAm level can be affected by genetic variation; although, how this differs by CpG dinucleotide density and genic location of the DNAm site is not well understood. Moreover, the effect of disease causing variants...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw072
更新日期:2016-06-15 00:00:00
abstract::The sensitivity of single-strand conformation polymorphism (SSCP) analysis for the detection of mutations in the porphobilinogen deaminase (PBGD) gene among Finnish patients with acute intermittent porphyria (AIP) was studied. 13 novel mutations including one de novo event, and six previously characterized mutations w...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.2.215
更新日期:1995-02-01 00:00:00
abstract::The von Hippel-Lindau (VHL) tumour suppressorgene product is believed to be involved in the down-regulation of transcriptional elongation by preventing the association of elongin B and C with the catalytic subunit elongin A. Alterations in the human VHL gene lead to VHL disease which is associated with various rare ne...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.2.229
更新日期:1999-02-01 00:00:00