TY  - JOUR
A1  - Stepniak, Beata
A1  - Kästner, Anne
A1  - Poggi, Giulia
A1  - Mitjans, Marina
A1  - Begemann, Martin
A1  - Hartmann, Annette
A1  - Van der Auwera, Sandra
A1  - Sananbenesi, Farahnaz
A1  - Krüger-Burg, Dilja
A1  - Matuszko, Gabriela
A1  - Brosi, Cornelia
A1  - Homuth, Georg
A1  - Völzke, Henry
A1  - Benseler, Fritz
A1  - Bagni, Claudia
A1  - Fischer, Utz
A1  - Dityatev, Alexander
A1  - Grabe, Hans-Jörgen
A1  - Rujescu, Dan
A1  - Fischer, Andre
A1  - Ehrenreich, Hannelore
T1  - Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes
JF  - EMBO Molecular Medicine
N2  - Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high-versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
KW  - permutation
KW  - miR-181
KW  - PGAS
KW  - FXR2
KW  - FXR1
KW  - FMR2
KW  - FMR1
KW  - identification
KW  - protein
KW  - fraxe mental retardation
KW  - CGG repeat
KW  - CPG Island
KW  - schizophrenia
KW  - expression
KW  - males
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136893
VL  - 7
IS  - 12
ER  - 
TY  - JOUR
A1  - Tolay, Nazife
A1  - Buchberger, Alexander
T1  - Comparative profiling of stress granule clearance reveals differential contributions of the ubiquitin system
JF  - Life Science Alliance
N2  - Stress granules (SGs) are cytoplasmic condensates containing untranslated mRNP complexes. They are induced by various proteotoxic conditions such as heat, oxidative, and osmotic stress. SGs are believed to protect mRNPs from degradation and to enable cells to rapidly resume translation when stress conditions subside. SG dynamics are controlled by various posttranslationalmodifications, but the role of the ubiquitin system has remained controversial. Here, we present a comparative analysis addressing the involvement of the ubiquitin system in SG clearance. Using high-resolution immuno-fluorescence microscopy, we found that ubiquitin associated to varying extent with SGs induced by heat, arsenite, H2O2, sorbitol, or combined puromycin and Hsp70 inhibitor treatment. SG-associated ubiquitin species included K48- and K63-linked conjugates, whereas free ubiquitin was not significantly enriched. Inhibition of the ubiquitin activating enzyme, deubiquitylating enzymes, the 26S proteasome and p97/VCP impaired the clearance of arsenite- and heat-induced SGs, whereas SGs induced by other stress conditions were little affected. Our data underline the differential involvement of the ubiquitin system in SG clearance, a process important to prevent the formation of disease-linked aberrant SGs.
KW  - phase transition
KW  - quality control
KW  - protein
KW  - inhibition
KW  - complexity
KW  - separation
KW  - diversity
KW  - autophagy
KW  - ALS
KW  - P97
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259810
VL  - 4
IS  - 5
ER  -