127 research outputs found
Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation
Aggregates of the RNA-binding protein TDP-43 (TAR DNAbinding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia. The process of TDP-43 aggregation
remains poorly understood, and whether it includes formation
of intermediate complexes is unknown. Here, we analyzed
aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the
initial time points before the formation of large aggregates. We
found that this early oligomerization stage is primarily driven by
TDP-43’s RNA-binding region. Specific binding to GU-rich
RNA strongly inhibited both TDP-43 oligomerization and
aggregation, suggesting that RNA interactions are critical for
maintaining TDP-43 solubility. Moreover, we analyzed TDP-43
liquid–liquid phase separation and detected similar detergentresistant oligomers upon maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers
form during the early steps of TDP-43 misfolding. Importantly,
the ALS-linked TDP-43 mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric
population and shortening the oligomeric phase. We also show
that aggregates generated from purified TDP-43 seed intracellular
aggregation detected by established TDP-43 pathology markers.
Remarkably, cytoplasmic aggregate seeding was detected earlier
for the A315T and M337V variants and was 50% more widespread
than forWTTDP-43 aggregates.We provide evidence for aninitial
step of TDP-43 self-assembly into intermediate oligomeric complexes, whereby these complexes may provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbationsin TDP-43 homeostasisin protein
aggregation and ALS-FTD pathogenesis
Novel fragmentation pathway for CID of (bn−1+Cat)+ ions from model, metal cationized peptides
Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer
Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents
Comparative studies of 193-nm photodissociation and TOF-TOFMS analysis of bradykinin analogues: The effects of charge site(s) and fragmentation timescales
Raloxifeno e osteoporose: revisão de um novo modulador seletivo do receptor de estrógeno
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