Abstract
BackgroundMutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 mutants can form cytoplasmic aggregates in vitro and in vivo.ResultsHere, we report that overexpression of WT or mutant UBQLN2 species enhanced nuclear factor κB (NF-κB) activation in Neuro2A cells. The inhibition of NF-κB stress-mediated activation with SB203580, a p38 MAPK inhibitor, demonstrated a role for MAPK in NF-κB activation by UBQLN2 species. Live cell imaging and microscopy showed that UBQLN2 aggregates are dynamic structures that promote cytoplasmic accumulation of TAR DNA-binding protein (TDP-43), a major component of ALS inclusion bodies. Furthermore, up-regulation of UBQLN2 species in neurons caused an ER-stress response and increased their vulnerability to death by toxic mediator TNF-α. Withaferin A, a known NF-κB inhibitor, reduced mortality of Neuro2A cells overexpressing UBQLN2 species.ConclusionsThese results suggest that UBQLN2 dysregulation in neurons can drive NF-κB activation and cytosolic TDP-43 aggregation, supporting the concept of pathway convergence in ALS pathogenesis. These Ubiquilin-2 pathogenic pathways might represent suitable therapeutic targets for future ALS treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0162-6) contains supplementary material, which is available to authorized users.
Highlights
Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
UBQLN2 up-regulation induces nuclear factor κB (NF-κB) activation We transfected Neuro2A cells with pCMV-hUBQLN2WT and mutant pCMV-hUBQLN2P497H plasmids to determine the effects of overexpressing hUBQLN2 species on activation of NF-κB signaling
NF-κB can be activated by many different pathways [11]. Because most of these pathways are induced by membrane receptors, like Interleukine-1(Il-1), Toll-like receptor (TLR), tumor-necrosis factor receptor (TNFR) and growth factor receptor (GF-R), we examined intracellular pathways activated in context of cellular stress
Summary
Mutations in the gene encoding Ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disorder. It is characterized by progressive degeneration of upper and lower motor neurons leading to paralysis and, to patient’s death within 2 to 5 years. 10 % of ALS cases are familial and 90 % are sporadic. Expanded hexanucleotide repeats in C9orf account for approximately 30 % of familial cases, mutations in superoxide dismutase 1 (SOD1) for 20 % whereas other genes like TAR DNAbinding protein (TDP-43), fused in sarcoma (FUS), p62/ SQSTM1 and Ubiquilin-2 (UBQLN2) account for less than 10 % [1]. Numerous cellular dysfunctions have been linked to ALS physiopathology including oxidative stress, protein inclusions, inflammatory processes, RNA processing and endoplasmic reticulum stress (ER-stress) [2]
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