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 FTLD-TDP and ALS; however, little is known about its role in disease pathogenesis. We have previously developed transgenic mice overexpressing low levels of TDP-25 (TgTDP-25(+/0)), which at 6 months of age show mild cognitive impairments and no motor deficits. To better understand the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP, we generated TDP-25 homozygous mice (TgTDP-25(+/+)), thereby further increasing TDP-25 expression. We found a gene-dosage effect on cognitive and motor function at 15 months of age, as the TgTDP-25(+/+) showed more severe spatial and working memory deficits as well as worse motor performance than TgTDP-25(+/0) mice. These behavioral deficits were associated with increased soluble levels of TDP-25 in the nucleus and cytosol. Notably, high TDP-25 levels were also linked to reduced autophagy induction and proteasome function, two events that have been associated with both ALS and FTLD-TDP. In summary, we present strong in vivo evidence that high levels of TDP-25 are sufficient to cause behavioral deficits and reduce function of two of the major protein turnover systems: autophagy and proteasome. These mice represent a new tool to study the role of TDP-25 in the pathogenesis of ALS and FTLD-TDP.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Caccamo A,Shaw DM,Guarino F,Messina A,Walker AW,Oddo Sdoi
10.1093/hmg/ddv193subject
Has Abstractpub_date
2015-08-15 00:00:00pages
4625-35issue
16eissn
0964-6906issn
1460-2083pii
ddv193journal_volume
24pub_type
杂志文章abstract::Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise a...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddv475
更新日期:2016-04-15 00:00:00
abstract::Sphingosine-1-phosphate (S1P) is a lipid-signaling molecule produced by sphingosine kinase in response to a wide number of stimuli. By acting through a family of widely expressed G protein-coupled receptors, S1P regulates diverse physiological processes. Here we examined the role of S1P signaling in neurodegeneration ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn126
更新日期:2008-08-01 00:00:00
abstract::Gelsolin amyloidosis is a dominantly inherited, incurable type of amyloidosis. A single point mutation in the gelsolin gene (G654A is most common) results in the loss of a Ca2+ binding site in the second gelsolin domain. Consequently, this domain partly unfolds and exposes an otherwise buried furin cleavage site at t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx056
更新日期:2017-04-01 00:00:00
abstract::During mitosis, Kif11, a kinesin motor protein, promotes bipolar spindle formation and chromosome movement, and during interphase, Kif11 mediates diverse trafficking processes in the cytoplasm. In humans, inactivating mutations in KIF11 are associated with (1) retinal hypovascularization with or without microcephaly a...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa018
更新日期:2020-05-08 00:00:00
abstract::Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr521
更新日期:2012-02-15 00:00:00
abstract::We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demonstrate that TOPORS...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq543
更新日期:2011-03-01 00:00:00
abstract::A recurrent t(9;22) (q22;q12) chromosome translocation has been described in extraskeletal myxoid chondrosarcoma (EMC). Fluorescent in situ hybridization experiments performed on one EMC tumour indicated that the chromosome 22 breakpoint occurred in the EWS gene. Northern blot analysis revealed an aberrant EWS transcr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.12.2219
更新日期:1995-12-01 00:00:00
abstract::The mitochondrial unfolded protein response (UPRmt) is a transcriptional program aimed at restoring proteostasis in mitochondria. Upregulation of mitochondrial matrix proteases and heat shock proteins was initially described. Soon thereafter, a distinct UPRmt induced by misfolded proteins in the mitochondrial intermem...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx049
更新日期:2017-04-01 00:00:00
abstract::Adult body height is a quantitative trait for which genome-wide association studies (GWAS) have identified numerous loci, primarily in European populations. These loci, comprising common variants, explain <10% of the phenotypic variance in height. We searched for novel associations between height and common (minor all...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu361
更新日期:2014-12-15 00:00:00
abstract::Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and l...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr385
更新日期:2011-12-01 00:00:00
abstract::Blepharophimosis syndrome (BPES, blepharophimosis eyelid syndrome) is a distinctive congenital eyelid malformation which can occur sporadically or be inherited in an autosomal dominant fashion. Previous reports have described associated cytogenetic abnormalities on chromosome 3q. We have ascertained and sampled two BP...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.3.443
更新日期:1995-03-01 00:00:00
abstract::Expression of misfolded protein in cultured cells frequently leads to the formation of juxtanuclear inclusions that have been termed 'aggresomes'. Aggresome formation is an active cellular response that involves trafficking of the offending protein along microtubules, reorganization of intermediate filaments and recru...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg074
更新日期:2003-04-01 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::Imputation is commonly used in genome-wide association studies to expand the set of genetic variants available for analysis. Larger and more diverse reference panels, such as the final Phase 3 of the 1000 Genomes Project, hold promise for improving imputation accuracy in genetically diverse populations such as Hispani...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw174
更新日期:2016-08-01 00:00:00
abstract::Ciliopathies form a group of inherited disorders sharing several clinical manifestations because of abnormal cilia formation or function, and few treatments have been successful against these disorders. Here, we report a mouse model with mutated Sclt1 gene, which encodes a centriole distal appendage protein important ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx183
更新日期:2017-08-01 00:00:00
abstract::Spinal muscular atrophy (SMA) is a common pediatric neuromuscular disorder caused by insufficient levels of the survival of motor neuron (SMN) protein. Studies involving SMA patients and animal models expressing the human SMN2 gene have yielded relatively little information about the earliest cellular consequences of ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn156
更新日期:2008-08-15 00:00:00
abstract::Deficiencies in the complex I (CI; NADH-ubiquinone oxidoreductase) of the respiratory chain are frequent causes of mitochondrial diseases and have been associated with other neurodegenerative disorders, such as Parkinson's disease. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex subunit 5 (NDUFA5) is a nuclear-e...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt526
更新日期:2014-03-15 00:00:00
abstract::Dysfunction of mitochondrial translation is an increasingly important molecular cause of human disease, but structural defects of mitochondrial ribosomal subunits are rare. We used next-generation sequencing to identify a homozygous variant in the mitochondrial small ribosomal protein 14 (MRPS14, uS14m) in a patient m...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy374
更新日期:2019-02-15 00:00:00
abstract::The gene responsible for Huntington disease has been localized to a 2.5 million base pair (Mb) region between the loci D4S10 and D4S168 on the short arm of chromosome 4. As part of a strategy to clone the HD gene on the basis of its chromosomal location, we isolated genomic DNA from the HD region as a set of overlappi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/1.3.149
更新日期:1992-06-01 00:00:00
abstract::Epidermolytic hyperkeratosis (EHK), (bullous congenital ichthyosiform erythroderma), is an autosomal dominant human skin disorder. Recently, we and others have described mutations in keratins 1 and 10 (K1 and K10) in patients with this disease. Structure-function models predict that these mutations would impair normal...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.12.2147
更新日期:1993-12-01 00:00:00
abstract::Despite the immense significance retrotransposons have had for genome evolution much about their biology is unknown, including the processes of forming their ribonucleoprotein (RNP) particles and transporting them about the cell. Suppression of retrotransposon expression, together with the presence of retrotransposon ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq048
更新日期:2010-05-01 00:00:00
abstract::Mutations in the WNK1 gene cause Gordon's syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting > 25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spa...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi187
更新日期:2005-07-01 00:00:00
abstract::LINE-1 elements comprise approximately 17% of human DNA and their mobility continues to impact genome evolution. However, little is known about the types of non-transformed cells that can support LINE-1 retrotransposition. Here, we show that human embryonic stem cells express endogenous LINE-1 elements and can accommo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm105
更新日期:2007-07-01 00:00:00
abstract::Multiple mitochondrial DNA deletions are associated with clinically heterogeneous disorders transmitted as mendelian traits. Dominant missense mutations were found in the gene encoding the heart and skeletal muscle-specific isoform of the adenine nucleotide translocator (ANT1) in families with autosomal dominant progr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi341
更新日期:2005-10-15 00:00:00
abstract::Four naturally occurring sequence variations have been found in the coding region of the DYT1 gene encoding torsinA. One of these, a 3 bp (DeltaGAG) deletion, underlies dominantly inherited cases of early-onset torsion dystonia. Others, including a single nucleotide polymorphism that replaces aspartic acid (D) at resi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl055
更新日期:2006-04-15 00:00:00
abstract::Homozygosity for Cst6 null alleles causes the phenotype of the ichq mouse, which is a model for human harlequin ichthyosis (OMIM 242500), a genetically heterogeneous group of keratinization disorders. Here we report evidence for the mechanism by which deficiency of the cysteine protease inhibitor cystatin M/E (the Cst...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh115
更新日期:2004-05-15 00:00:00
abstract::We have used inbred and congenic rat strains in F(2) segregation studies to discover epistasis in a polygenic model of hypertension. Previously, we have found evidence that the presence of a blood pressure quantitative trait locus (QTL) on chromosome 1 is conditional upon the allele status of chromosome 10. To prove t...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddg041
更新日期:2003-02-15 00:00:00
abstract::Choroideremia (CHM) is an X-linked progressive eye disorder which results from defects in the human Rab escort protein-1 (REP-1) gene. A gene targeting approach was used to disrupt the mouse chm/rep-1 gene. Chimeric males transmitted the mutated gene to their carrier daughters but, surprisingly, these heterozygous fem...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.6.851
更新日期:1997-06-01 00:00:00
abstract::Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We c...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp052
更新日期:2009-04-15 00:00:00
abstract::Leptomeningeal glioneuronal heterotopia (LGH) is a focal malformation of the cerebral cortex and frequently found in patients with thanatophoric dysplasia (TD). The pathophysiological mechanisms underlying LGH formation are still largely unclear because of difficulties in obtaining brain samples from human TD patients...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy014
更新日期:2018-03-15 00:00:00