Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.

Abstract:

:Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants-WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick's disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Koller EJ,Gonzalez De La Cruz E,Machula T,Ibanez KR,Lin WL,Williams T,Riffe CJ,Ryu D,Strang KH,Liu X,Janus C,Golde TE,Dickson D,Giasson BI,Chakrabarty P

doi

10.1093/hmg/ddz151

subject

Has Abstract

pub_date

2019-10-01 00:00:00

pages

3255-3269

issue

19

eissn

0964-6906

issn

1460-2083

pii

5526800

journal_volume

28

pub_type

杂志文章
  • Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space.

    abstract::Huntington disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG trinucleotide repeat in the first exon of the HD gene, which results in a toxic polyglutamine stretch within huntingtin, the protein it encodes. Understanding the normal function of this essential protein is vital to u...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddl467

    authors: Strehlow AN,Li JZ,Myers RM

    更新日期:2007-02-15 00:00:00

  • Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity.

    abstract::Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by polyglutamine expansion in the disease protein, huntingtin. In HD patients and transgenic mice, the affected neurons form characteristic ubiquitin-positive nuclear inclusions (NIs). We have established ecdysone-inducible stable mou...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/9.13.2009

    authors: Jana NR,Tanaka M,Wang Gh,Nukina N

    更新日期:2000-08-12 00:00:00

  • Inter- and intrachromosomal sub-telomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis.

    abstract::The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD) is causally related to a short Eco RI fragment detected by probe p13E-11. This remnant fragment is the result of a deletion of an integral number of tandemly arrayed 3.3 kb repeat units (D4Z4) on 4q35. Despite intensive efforts, no transcrib...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/7.8.1207

    authors: Lemmers RJ,van der Maarel SM,van Deutekom JC,van der Wielen MJ,Deidda G,Dauwerse HG,Hewitt J,Hofker M,Bakker E,Padberg GW,Frants RR

    更新日期:1998-08-01 00:00:00

  • Genetic and chemical rescue of the Saccharomyces cerevisiae phenotype induced by mitochondrial DNA polymerase mutations associated with progressive external ophthalmoplegia in humans.

    abstract::The human POLG gene encodes the catalytic subunit of mitochondrial DNA polymerase gamma (pol gamma). Mutations in pol gamma are associated with a spectrum of disease phenotypes including autosomal dominant and recessive forms of progressive external ophthalmoplegia, spino-cerebellar ataxia and epilepsy, and Alpers-Hut...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddl219

    authors: Baruffini E,Lodi T,Dallabona C,Puglisi A,Zeviani M,Ferrero I

    更新日期:2006-10-01 00:00:00

  • The effect of food intake on gene expression in human peripheral blood.

    abstract::Human gene expression traits have been shown to be dependent on gender, age and time of day in blood and other tissues. However, other factors that may impact gene expression have not been systematically explored. For example, in studies linking blood gene expression to obesity related traits, whether the fasted or fe...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddp476

    authors: Leonardson AS,Zhu J,Chen Y,Wang K,Lamb JR,Reitman M,Emilsson V,Schadt EE

    更新日期:2010-01-01 00:00:00

  • The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1.

    abstract::Mutations in the DFNB31 gene encoding the PDZ scaffold protein whirlin are causative for hearing loss in man and mouse. Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear, though its complete spatial and temporal expression patterns remained elusive. H...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddi490

    authors: van Wijk E,van der Zwaag B,Peters T,Zimmermann U,Te Brinke H,Kersten FF,Märker T,Aller E,Hoefsloot LH,Cremers CW,Cremers FP,Wolfrum U,Knipper M,Roepman R,Kremer H

    更新日期:2006-03-01 00:00:00

  • Alteration of performance in a mouse model of Emery-Dreifuss muscular dystrophy caused by A-type lamins gene mutation.

    abstract::Autosomal Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humero-peroneal muscle wasting and weakness, early joint contractures and dilated ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddz056

    authors: Thomasson R,Vignier N,Peccate C,Mougenot N,Noirez P,Muchir A

    更新日期:2019-07-01 00:00:00

  • Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing.

    abstract::Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on pre-mRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor transformer2-beta1 (tra2-beta1) via a phylogenetically conserved RVDF se...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddm284

    authors: Novoyatleva T,Heinrich B,Tang Y,Benderska N,Butchbach ME,Lorson CL,Lorson MA,Ben-Dov C,Fehlbaum P,Bracco L,Burghes AH,Bollen M,Stamm S

    更新日期:2008-01-01 00:00:00

  • c-Myc is a regulator of the PKD1 gene and PC1-induced pathogenesis.

    abstract::Autosomal dominant polycystic kidney disease (ADPKD) is among the most common monogenic disorders mainly associated with PKD1/PC1 mutations. We show herein that renal regulation in Pc1 dosage-reduced and -increased mouse models converge toward stimulation of c-Myc expression along with β-catenin, delineating c-Myc as ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddy379

    authors: Parrot C,Kurbegovic A,Yao G,Couillard M,Côté O,Trudel M

    更新日期:2019-03-01 00:00:00

  • Comparative analysis and genomic structure of the tuberous sclerosis 2 (TSC2) gene in human and pufferfish.

    abstract::Germ-line mutations of the TSC2 tumour suppressor gene have been identified in humans with tuberous sclerosis and in the Eker rat. Tuberin, the human TSC2 gene product, has a small region of homology with rap1GAP and stimulates rap1 GTPase activity in vitro, suggesting that one of its cellular roles is to function as ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/5.1.131

    authors: Maheshwar MM,Sandford R,Nellist M,Cheadle JP,Sgotto B,Vaudin M,Sampson JR

    更新日期:1996-01-01 00:00:00

  • Neural cell recognition molecule L1: relating biological complexity to human disease mutations.

    abstract::Human single gene disorders that affect the nervous system provide a host of natural mutations that can be deployed in the quest to understand its development and function. A paradigm for this approach is the study of disorders caused by mutations in the gene for the neural cell recognition molecule L1. L1 is the foun...

    journal_title:Human molecular genetics

    pub_type: 杂志文章,评审

    doi:10.1093/hmg/9.6.879

    authors: Kenwrick S,Watkins A,De Angelis E

    更新日期:2000-04-12 00:00:00

  • Over-expression of angiotensin converting enzyme-1 augments cardiac hypertrophy in transgenic rats.

    abstract::Increased cardiac angiotensin converting enzyme-1 (ACE1) is found in individuals who carry a deletion in intron 16 of ACE1 gene or in individuals who suffer from cardiac disorders, such as hypertrophy. However, whether a single increase in ACE1 expression leads to spontaneous cardiac defects remains unknown. To determ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddh147

    authors: Tian XL,Pinto YM,Costerousse O,Franz WM,Lippoldt A,Hoffmann S,Unger T,Paul M

    更新日期:2004-07-15 00:00:00

  • A common molecular basis for rearrangement disorders on chromosome 22q11.

    abstract::The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der() syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/8.7.1157

    authors: Edelmann L,Pandita RK,Spiteri E,Funke B,Goldberg R,Palanisamy N,Chaganti RS,Magenis E,Shprintzen RJ,Morrow BE

    更新日期:1999-07-01 00:00:00

  • Calcium dynamics change in degenerating cone photoreceptors.

    abstract::Cone photoreceptors (cones) are essential for high-resolution daylight vision and colour perception. Loss of cones in hereditary retinal diseases has a dramatic impact on human vision. The mechanisms underlying cone death are poorly understood, and consequently, there are no treatments available. Previous studies sugg...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddw219

    authors: Kulkarni M,Trifunović D,Schubert T,Euler T,Paquet-Durand F

    更新日期:2016-09-01 00:00:00

  • Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP.

    abstract::In mammals, sperm-oocyte fusion initiates Ca(2+) oscillations leading to a series of events called oocyte activation, which is the first stage of embryo development. Ca(2+) signaling is elicited by the delivery of an oocyte-activating factor by the sperm. A sperm-specific phospholipase C (PLCZ1) has emerged as the lik...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddv617

    authors: Escoffier J,Lee HC,Yassine S,Zouari R,Martinez G,Karaouzène T,Coutton C,Kherraf ZE,Halouani L,Triki C,Nef S,Thierry-Mieg N,Savinov SN,Fissore R,Ray PF,Arnoult C

    更新日期:2016-03-01 00:00:00

  • LKB1-regulated adaptive mechanisms are essential for neuronal survival following mitochondrial dysfunction.

    abstract::Mitochondrial dysfunction plays an important role in the etiology of neurodegenerative diseases. However, the progressive nature of neuronal loss in genetic models of mitochondrial dysfunction suggests the presence of compensatory mechanisms promoting neuronal survival under these conditions. Here, we identified the e...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/dds500

    authors: Germain M,Nguyen AP,Khacho M,Patten DA,Screaton RA,Park DS,Slack RS

    更新日期:2013-03-01 00:00:00

  • A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis.

    abstract::Periodontitis is a widespread, complex inflammatory disease of the mouth, which results in a loss of gingival tissue and alveolar bone, with aggressive periodontitis (AgP) as its most severe form. To identify genetic risk factors for periodontitis, we conducted a genome-wide association study in German AgP patients. W...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddp508

    authors: Schaefer AS,Richter GM,Nothnagel M,Manke T,Dommisch H,Jacobs G,Arlt A,Rosenstiel P,Noack B,Groessner-Schreiber B,Jepsen S,Loos BG,Schreiber S

    更新日期:2010-02-01 00:00:00

  • Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy.

    abstract::Dilated cardiomyopathy (DCM) due to mutations in RBM20, a gene encoding an RNA-binding protein, is associated with high familial penetrance, risk of progressive heart failure and sudden death. Although genetic investigations and physiological models have established the linkage of RBM20 with early-onset DCM, the under...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu091

    authors: Beraldi R,Li X,Martinez Fernandez A,Reyes S,Secreto F,Terzic A,Olson TM,Nelson TJ

    更新日期:2014-07-15 00:00:00

  • Mice lacking cyclin-dependent kinase-like 5 manifest autistic and ADHD-like behaviors.

    abstract::Neurodevelopmental disorders frequently share common clinical features and appear high rate of comorbidity, such as those present in patients with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). While characterizing behavioral phenotypes in the mouse model of cyclin-dependent kinas...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddx279

    authors: Jhang CL,Huang TN,Hsueh YP,Liao W

    更新日期:2017-10-15 00:00:00

  • Chemical genetics unveils a key role of mitochondrial dynamics, cytochrome c release and IP3R activity in muscular dystrophy.

    abstract::Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by mutations in the dystrophin gene. The subcellular mechanisms of DMD remain poorly understood and there is currently no curative treatment available. Using a Caenorhabditis elegans model for DMD as a pharmacologic and genetic tool, we found that cyc...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddt302

    authors: Giacomotto J,Brouilly N,Walter L,Mariol MC,Berger J,Ségalat L,Becker TS,Currie PD,Gieseler K

    更新日期:2013-11-15 00:00:00

  • Identification of a novel, methylation-dependent, RUNX2 regulatory region associated with osteoarthritis risk.

    abstract::Osteoarthritis (OA) is a common, multifactorial and polygenic skeletal disease that, in its severest form, requires joint replacement surgery to restore mobility and to relieve chronic pain. Using tissues from the articulating joints of 260 patients with OA and a range of in vitro experiments, including CRISPR-Cas9, w...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddy257

    authors: Rice SJ,Aubourg G,Sorial AK,Almarza D,Tselepi M,Deehan DJ,Reynard LN,Loughlin J

    更新日期:2018-10-01 00:00:00

  • L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1.

    abstract::l-2-Hydroxyglutaric aciduria (l-2-HGA) is characterized by progressive deterioration of central nervous system function including epilepsy and macrocephaly in 50% of cases, and elevated levels of l-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid (CSF). Nuclear magnetic resonance imaging shows distinct a...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddh300

    authors: Topçu M,Jobard F,Halliez S,Coskun T,Yalçinkayal C,Gerceker FO,Wanders RJ,Prud'homme JF,Lathrop M,Ozguc M,Fischer J

    更新日期:2004-11-15 00:00:00

  • Defects in myelination, paranode organization and Purkinje cell innervation in the ether lipid-deficient mouse cerebellum.

    abstract::Ether lipids (ELs), particularly plasmalogens, are essential constituents of the mammalian central nervous system. The physiological role of ELs, in vivo, however is still enigmatic. In the present study, we characterized a mouse model carrying a targeted deletion of the peroxisomal dihydroxyacetonephosphate acyltrans...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddp110

    authors: Teigler A,Komljenovic D,Draguhn A,Gorgas K,Just WW

    更新日期:2009-06-01 00:00:00

  • Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31-34.

    abstract::We performed a whole genome microsatellite marker scan in six multiplex families with bipolar (BP) mood disorder ascertained in Antioquia, a historically isolated population from North West Colombia. These families were characterized clinically using the approach employed in independent ongoing studies of BP in the cl...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddl254

    authors: Herzberg I,Jasinska A,García J,Jawaheer D,Service S,Kremeyer B,Duque C,Parra MV,Vega J,Ortiz D,Carvajal L,Polanco G,Restrepo GJ,López C,Palacio C,Levinson M,Aldana I,Mathews C,Davanzo P,Molina J,Fournier E,Bejar

    更新日期:2006-11-01 00:00:00

  • Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).

    abstract::Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is clinically and genetically heterogeneous and can appear as syndromic or non-syndromic. Mucopolysaccharidosis type IIIC (MPS IIIC) is a lethal disorder, caused by mutations in the heparan-alpha-glucosaminide N-acetyltransferase (HGSNA...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddv118

    authors: Haer-Wigman L,Newman H,Leibu R,Bax NM,Baris HN,Rizel L,Banin E,Massarweh A,Roosing S,Lefeber DJ,Zonneveld-Vrieling MN,Isakov O,Shomron N,Sharon D,Den Hollander AI,Hoyng CB,Cremers FP,Ben-Yosef T

    更新日期:2015-07-01 00:00:00

  • Allelic imbalance in BRCA1 and BRCA2 gene expression is associated with an increased breast cancer risk.

    abstract::The contribution of BRCA1 and BRCA2 to familial and non-familial forms of breast cancer has been difficult to accurately estimate because of the myriad of potential genetic and epigenetic mechanisms that can ultimately influence their expression and involvement in cellular activities. As one of these potential mechani...

    journal_title:Human molecular genetics

    pub_type: 临床试验,杂志文章

    doi:10.1093/hmg/ddn022

    authors: Chen X,Weaver J,Bove BA,Vanderveer LA,Weil SC,Miron A,Daly MB,Godwin AK

    更新日期:2008-05-01 00:00:00

  • Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway.

    abstract::By GenBank database searches and PCR, we have identified a novel human Bcl2-like gene, Bcl2-L-10, which contains conserved BH4, BH1 and BH2 domains but lacks BH3 domain. The Bcl2-L-10 gene has been assigned to chromosome 15q21.2. Transfection experiments demonstrated that Bcl2-L-10 can block apoptosis induced by inter...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/10.21.2329

    authors: Zhang H,Holzgreve W,De Geyter C

    更新日期:2001-10-01 00:00:00

  • Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy.

    abstract::Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone (or dihydrotestost...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddu419

    authors: Giorgetti E,Rusmini P,Crippa V,Cristofani R,Boncoraglio A,Cicardi ME,Galbiati M,Poletti A

    更新日期:2015-01-01 00:00:00

  • The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex.

    abstract::The biogenesis of the mitochondrial inner membrane is dependent on two distinct 70 kDa protein complexes. TIMM8a partners with TIMM13 in the mitochondrial intermembrane space to form a 70 kDa complex and facilitates the import of the inner membrane substrate TIMM23. We have identified a new class of substrates, citrin...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/ddh217

    authors: Roesch K,Hynds PJ,Varga R,Tranebjaerg L,Koehler CM

    更新日期:2004-09-15 00:00:00

  • Severe (type III) osteogenesis imperfecta due to glycine substitutions in the central domain of the collagen triple helix.

    abstract::The molecular defects responsible for three cases of severe (type III) osteogenesis imperfecta (OI) were investigated. The mutation sites were localized in pro alpha 1(I) and pro alpha 2(I) mRNA molecules, respectively, by chemical cleavage of mismatch in heteroduplex nucleic acids. Mutation identification was achieve...

    journal_title:Human molecular genetics

    pub_type: 杂志文章

    doi:10.1093/hmg/3.12.2201

    authors: Forlino A,Zolezzi F,Valli M,Pignatti PF,Cetta G,Brunelli PC,Mottes M

    更新日期:1994-12-01 00:00:00