TTR (transthyretin) leads the autophagy disaster relief team against TARDBP/TDP-43 proteinopathy.

TTR (transthyretin) strikes a neuroprotective function in the prevention of amyloid-β (Aβ) deposition in Alzheimer disease (AD). Perturbation of the stringently controlled TARDBP/TDP-43 (TAR DNA binding protein) expression gives rise to cytoplasmic aggregation, characterized by TARDBP proteinopathy affiliated with several neurological disorders, including frontotemporal lobar degeneration with TARDBP pathology (FTLD-TDP) and amyotrophic lateral sclerosis/ALS. Proposedly, TTR can maintain cellular proteostasis susceptible to TARDBP aggregates and initiate its removal.

Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP.

TAR DNA-binding protein-43 (TDP-43) proteinopathies are accompanied by the pathological hallmark of cytoplasmic inclusions in the neurodegenerative diseases, including frontal temporal lobar degeneration-TDP and amyotrophic lateral sclerosis. We found that transthyretin accumulates with TDP-43 cytoplasmic inclusions in frontal temporal lobar degeneration-TDP human patients and transgenic mice, in which transthyretin exhibits dramatic expression decline in elderly mice. The upregulation of transthyretin expression was demonstrated to facilitate the clearance of cytoplasmic TDP-43 inclusions through autophagy, in which transthyretin induces autophagy upregulation via ATF4.

Structure-Based Analysis of Protein Cluster Size for Super-Resolution Microscopy in the Nervous System.

To overcome the diffraction limit and resolve target structures in greater detail, far-field super-resolution techniques such as stochastic optical reconstruction microscopy (STORM) have been developed, and different STORM algorithms have been developed to deal with the various problems that arise. In particular, the effect of the local structure is an important issue. For objects with closely correlated distributions, simple Gaussian-based localization algorithms often used in STORM imaging misinterpret overlapping point spread functions (PSFs) as one, which limits the ability of super-resolution imaging to resolve nanoscale local structures and leads to inaccurate length measurements.

Somatosensory Cortical Electrical Stimulation After Reperfusion Attenuates Ischemia/Reperfusion Injury of Rat Brain.

Ischemic stroke is an important cause of death and disability worldwide. Early reperfusion by thrombolysis or thrombectomy has improved the outcome of acute ischemic stroke. However, the therapeutic window for reperfusion therapy is narrow, and adjuvant therapy for neuroprotection is demanded.

TDP-43 proteinopathy impairs mRNP granule mediated postsynaptic translation and mRNA metabolism.

Local protein synthesis and mRNA metabolism mediated by mRNP granules in the dendrites and the postsynaptic compartment is essential for synaptic remodeling and plasticity in neuronal cells. Dysregulation of these processes caused by TDP-43 proteinopathy leads to neurodegenerative diseases, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Using biochemical analysis and imaging techniques, including super-resolution microscopy, we provide evidence, for the first time, for the postsynaptic localization of TDP-43 in mammalian synapses and we show that TDP-43 is a component of neuronal mRNP granules.

Solution structure and backbone dynamics of the DNA-binding domain of FOXP1: insight into its domain swapping and DNA binding.

FOXP1 belongs to the P-subfamily of forkhead transcription factors and contains a conserved forkhead DNA-binding domain. According to size exclusion chromatography analysis, the forkhead domain of FOXP1 existed as a mixture of monomer and dimer. The dissociation constants of the forkhead domain of wild-type, C61S, and C61Y mutants of FOXP1 were 27.

Expression in Pichia pastoris and characterization of APETx2, a specific inhibitor of acid sensing ion channel 3.

Acid sensing ion channels (ASICs) are family of proteins predominantly present in the central and peripheral nervous system. They are known to play important roles in the pathophysiology of pain and ischemic stroke. APETx2 is a potent and selective inhibitor of ASIC3-containing channels and was isolated from sea anemone Anthopleura elegantissima.

Lys-64 of the A chain is involved in the enzymatic activity and neurotoxic effect of beta-bungarotoxin.

Two beta-bungarotoxin isotoxins BM12 and BM13 were isolated from Bungarus multicinctus (Taiwan banded krait) venom by sequential chromatography on ion-exchange and reverse phase columns. The two toxins have the same A chain, but different B chains. Different phospholipase A2 activity and different potencies in inhibiting the spontaneous enhancement of spontaneous synaptic current frequency and muscle contraction were observed for BM12 and BM13.

The structural events associated with the binding of divalent cations to beta-bungarotoxin.

In order to address the mechanism why the Ca2+ was crucial for the manifestation of the phospholipase A2 (PLA2) activity of beta-bungarotoxin (beta-BuTx), four divalent cations were used to assess their influences on the catalytic activity and the fine structures of beta-BuTx. Substitution Mg2+ or Sr2+ for Ca2+ in the substrate solution was found to cause a decrease in the PLA2 activity to approximately 15 or 6% of that in the presence of Ca2+. However, only marginally detectable PLA2 activity was observed with the addition of Ba2+.

Both A chain and B chain of beta-bungarotoxin are functionally involved in the facilitation of spontaneous transmitter release in Xenopus nerve-muscle cultures.

In the present study, Xenopus nerve-muscle cultures were used to explore the functional roles of A chain (a phospholipase A(2) subunit) and B chain (a non-phospholipase A(2) subunit) of Bungarus multicinctus beta-bungarotoxin. It was found that beta-bungarotoxin induced an increment of the frequency of spontaneous synaptic currents (SSCs) in the nerve-muscle cultures. Modification of beta-bungarotoxin with pyridoxal-5'-phosphate or substitution of Ca(2+) with Ba(2+) in buffer abolished the phospholipase A(2) activity of beta-bungarotoxin and the facilitatory phase of SSC as well.

The organization of the genes encoding the A chains of beta-bungarotoxins: evidence for the skipping of exon.

Bungarus multicinctus (Taiwan banded krait) beta-bungarotoxins consist of two dissimilar polypeptide chains, A and B. The A chain is structurally homologous to phospholipase A(2) (PLA(2)) enzymes. The structural organization of the genes encoding A1, A2 and A8 chains are reported in this study.