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 dihydrotestosterone), and the polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons, testosterone triggers nuclear toxicity by inducing AR nuclear translocation. Thus, (i) prevention of ARpolyQ nuclear localization, combined with (ii) an increased ARpolyQ cytoplasmic clearance, should reduce its detrimental activity. Using the antiandrogen Bicalutamide (Casodex(®)), which slows down AR activation and nuclear translocation, and the disaccharide trehalose, an autophagy activator, we found that, in motoneurons, the two compounds together reduced ARpolyQ insoluble forms with higher efficiency than that obtained with single treatments. The ARpolyQ clearance was mediated by trehalose-induced autophagy combined with the longer cytoplasmic retention of ARpolyQ bound to Bicalutamide. This allows an increased recognition of misfolded species by the autophagic system prior to their migration into the nucleus. Interestingly, the combinatory use of trehalose and Bicalutamide was also efficient in the removal of insoluble species of AR with a very long polyQ (Q112) tract, which typically aggregates into the cell nuclei. Collectively, these data suggest that the combinatory use of Bicalutamide and trehalose is a novel approach to facilitate ARpolyQ clearance that has to be tested in other cell types target of SBMA (i.e. muscle cells) and in vivo in animal models of SBMA.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Giorgetti E,Rusmini P,Crippa V,Cristofani R,Boncoraglio A,Cicardi ME,Galbiati M,Poletti Adoi
10.1093/hmg/ddu419subject
Has Abstractpub_date
2015-01-01 00:00:00pages
64-75issue
1eissn
0964-6906issn
1460-2083pii
ddu419journal_volume
24pub_type
杂志文章abstract::Human leukocyte antigen (HLA)-E is a non-classical major histocompatibility complex class I (Ib) molecule, which plays an important role in immunosuppression. In this study, we investigated the immunomodulating effect of HLA-E in a xenogeneic system, using human placental artery-derived endothelial (hPAE) cells expres...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq458
更新日期:2011-01-15 00:00:00
abstract::The effect of endogenous nitric oxide synthase (NOS) on cardiac contractility and architecture has been a matter of debate. A role for NOS in cardiac hypertrophy has recently been demonstrated by studies which have shown hypertrophic cardiomyopathy (HCM) with altered contractility in constitutive NOS (cNOS) knockout m...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh014
更新日期:2004-01-15 00:00:00
abstract::Recombination was measured across nine intervals in the human beta-globin gene cluster by single-sperm analysis. A recombination fraction of approximately 0.9% was calculated across an approximately 11 kb region using a new method to estimate recombination fractions from single-sperm typing data. No recombination was ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.3.207
更新日期:2002-02-01 00:00:00
abstract::Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.4.467
更新日期:2000-03-01 00:00:00
abstract::To enhance our understanding of the autosomal recessive limb-girdle muscular dystrophy (LGMD), patients from six genetically distinct forms (LGMD2A to LGMD2F) were studied with antibodies directed against four sarcoglycan subunits (alpha-, beta-, gamma-, delta-SG), dystrophin, beta-dystroglycan (beta-DG) and merosin. ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.12.1963
更新日期:1996-12-01 00:00:00
abstract::Huntingtin interacting protein 14 (HIP14, ZDHHC17) is a huntingtin (HTT) interacting protein with palmitoyl transferase activity. In order to interrogate the function of Hip14, we generated mice with disruption in their Hip14 gene. Hip14-/- mice displayed behavioral, biochemical and neuropathological defects that are ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr308
更新日期:2011-10-15 00:00:00
abstract::We examined the imprinting status of the insulin-like growth factor II gene (IGF2) in a series of 20 human breast disease samples to determine if disrupted imprinting (as evidenced by biallelic expression), was a demonstrable mechanism of altered gene expression. These samples included benign (n = 7) and malignant bre...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.8.1123
更新日期:1996-08-01 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::Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease characterized by the loss of motor neurons. Motor neuron degeneration is probably both a cell autonomous and a non-autonomous event. Therefore, manipulating the diseased microenvironment via non-neural cell replacement could be a th...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq293
更新日期:2010-10-01 00:00:00
abstract::Primary open-angle glaucoma (POAG) is a complex disorder characterized by a progressive and treatable degeneration of the optic nerve. TIGR/myocilin (MYOC) gene mutations are found in approximately 4% of all POAG patients. Populations with frequent founder effects, such as the French-Canadians, offer unique advantages...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.18.2077
更新日期:2002-09-01 00:00:00
abstract::BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants include growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz202
更新日期:2019-11-15 00:00:00
abstract::Fatty liver has been associated with unfavourable metabolic changes in circulation. To provide insights in fatty liver-related metabolic deviations, we compared metabolic association profile of fatty liver versus metabolic association profiles of genotypes increasing the risk of non-alcoholic fatty liver disease (NAFL...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy124
更新日期:2018-06-15 00:00:00
abstract::The autosomal recessive mouse mutation retinal degeneration 6 (rd6) causes small, white retinal spots and progressive photoreceptor degeneration similar to that observed in human flecked retinal diseases. Using a positional cloning approach, we determined that rd6 mice carry a splice donor mutation in the mouse homolo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.16.1879
更新日期:2002-08-01 00:00:00
abstract::Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25-30% of POI cases, demonstrating the high genetic heterogeneity of POI an...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa153
更新日期:2020-09-29 00:00:00
abstract::Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Previous data have shown that MECP2 RNA is present in all mouse and human tissues tested, but the timing of expression and regional distribution have not been explored. We investigated the spatial...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.2.115
更新日期:2002-01-15 00:00:00
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
更新日期:2004-11-15 00:00:00
abstract::Mutations in enzymes involved in sphingolipid metabolism and trafficking cause a variety of neurological disorders, but details of the molecular pathophysiology remain obscure. SPTLC1 encodes one subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in sphingolipid synthesis. Mutations in SPTLC1 cause...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddi380
更新日期:2005-11-15 00:00:00
abstract::Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (αDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective αDG glycosylation and reduced ligand binding by α...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt021
更新日期:2013-05-01 00:00:00
abstract::We report identification of a novel genetic locus (GLC1P) for normal tension glaucoma (NTG) on chromosome 12q14 using linkage studies of an African-American pedigree (maximum non-parametric linkage score = 19.7, max LOD score = 2.7). Subsequent comparative genomic hybridization and quantitative polymerase chain reacti...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr123
更新日期:2011-06-15 00:00:00
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
更新日期:1999-07-01 00:00:00
abstract::Craniosynostosis, the abnormal development of the calvarial sutures, occurs as an autosomal dominant trait in many clinically distinct syndromes. We performed linkage analysis of a provisionally novel type of autosomal dominant craniosynostosis in a large three generational family. Linkage was established between the ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.2.119
更新日期:1993-02-01 00:00:00
abstract::Current evidence indicates that excess brain cholesterol regulates amyloid-β (Aβ) deposition, which in turn can regulate cholesterol homeostasis. Moreover, Aβ neurotoxicity is potentiated, in part, by mitochondrial glutathione (mGSH) depletion. To better understand the relationship between alterations in cholesterol h...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt201
更新日期:2013-09-01 00:00:00
abstract::The parent of origin-dependent expression of the IGF2 and H19 genes is controlled by the imprinting centre 1 (IC1) consisting in a methylation-sensitive chromatin insulator. Deletions removing part of IC1 have been found in patients affected by the overgrowth- and tumour-associated Beckwith-Wiedemann syndrome (BWS). T...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn031
更新日期:2008-05-15 00:00:00
abstract::Recent studies in mice have clearly demonstrated that eliminating Apo E alters the rate, character and distribution of A beta deposits. In the present study, we asked whether elevating the levels of Apo E can, in a dominant fashion, influence amyloid deposition. We expressed human (Hu) Apo E4 via the mouse prion prote...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/10.22.2525
更新日期:2001-10-15 00:00:00
abstract::The internal structure of different alleles of the minisatellite present at the 3' end of the apolipoprotein B (ApoB) gene has been analysed by different approaches including sequencing. The repeat unit arrangements of the minisatellite on 570 chromosomes belonging to European and African populations were thus determi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/5.1.61
更新日期:1996-01-01 00:00:00
abstract::Although genetic variations in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neu...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds320
更新日期:2012-11-01 00:00:00
abstract::Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.12.2069
更新日期:1997-11-01 00:00:00
abstract::Mutations in both alleles of the tumour suppressor gene coding for merlin/schwannomin, an ERM family protein, cause the hereditary disease neurofibromatosis type 2 (NF2). NF2 is characterized by the development of multiple nervous system tumours especially vestibular schwannomas. Efficient oncoretrovirus-mediated gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/11.1.69
更新日期:2002-01-01 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::The most common form of hereditary haemochromatosis is an adult-onset condition usually associated with the HFE C282Y/C282Y genotype. The phenotypic expression of this genotype is heterogeneous and depends on a complex interplay of genetic and non-genetic factors. The aim of the present study was to determine if mutat...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddh206
更新日期:2004-09-01 00:00:00