Ubiquitinylation of α-Synuclein by Carboxyl Terminus Hsp70-Interacting Protein (CHIP) Is Regulated by Bcl-2-Associated Athanogene 5 (BAG5)

Parkinson's disease (PD) is a common neurodegenerative condition in which abnormalities in protein homeostasis, or proteostasis, may lead to accumulation of the protein α-synuclein (α-syn). Mutations within or multiplications of the gene encoding α-syn are known to cause genetic forms of PD and polymorphisms in the gene are recently established risk factors for idiopathic PD. α-syn is a major component of Lewy bodies, the intracellular proteinaceous inclusions which are pathological hallmarks of most forms of PD. Recent evidence demonstrates that α-syn can self associate into soluble oligomeric species and implicates these α-syn oligomers in cell death. We have previously shown that carboxyl terminus of Hsp70-interacting protein (CHIP), a co-chaperone molecule with E3 ubiquitin ligase activity, may reduce the levels of toxic α-syn oligomers. Here we demonstrate that α-syn is ubiquitinylated by CHIP both in vitro and in cells. We find that the products from ubiquitinylation by CHIP include both monoubiquitinylated and polyubiquitinylated forms of α-syn. We also demonstrate that CHIP and α-syn exist within a protein complex with the co-chaperone bcl-2-associated athanogene 5 (BAG5) in brain. The interaction of CHIP with BAG5 is mediated by Hsp70 which binds to the tetratricopeptide repeat domain of CHIP and the BAG domains of BAG5. The Hsp70-mediated association of BAG5 with CHIP results in inhibition of CHIP E3 ubiquitin ligase activity and subsequently reduces α-syn ubiquitinylation. Furthermore, we use a luciferase-based protein-fragment complementation assay of α-syn oligomerization to investigate regulation of α-syn oligomers by CHIP in living cells. We demonstrate that BAG5 mitigates the ability of CHIP to reduce α-syn oligomerization and that non-ubiquitinylated α-syn has an increased propensity for oligomerization. Thus, our results identify CHIP as an E3 ubiquitin ligase of α-syn and suggest a novel function for BAG5 as a modulator of CHIP E3 ubiquitin ligase activity with implications for CHIP-mediated regulation of α-syn oligomerization

Structural basis of mitochondrial receptor binding and constriction by DRP1.

Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signalling element and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51. After co-assembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery

Research Notes : Correlation among seed yield, seed quality and nutritional traits in soybean

Introduction : In the present communication, the information obtained on correlations among 14 traits related to seed yield, seed quality and nu-trition in soybean germplasm has been discussed, The information on the nature of variation for these traits in the above material has been reported earlier (Rana et al., 1981). Materials and methods : The materials and methods were reported earlier by Rana et al. (1981)

Research Notes: Variation for seed yield, its quality and nutritional traits in soybeans

To bring about genetic improvement for any economic trait in economic plants, the foremost prerequisite is the presence of sufficient amount of genetic variability for the trait under improvement in the organism t o be improved. In the present investigation, an attempt has been made to get the information on nature and magnitude of variability for various seed quality traits along with seed yield traits in the soybean germplasm maintained at the Himachal Pradesh Agricultural University, Palampur. Materials and methods: The material for the present study consisted of 250 diverse genotypes of soybeans of both indigenous and exotic origin , and 5 standard checks

Hydroxychloroquine for chronic myeloid leukemia: complete cure on the horizon?

No abstract available

Direct detection of alpha synuclein oligomers in vivo

Background: Rat models of Parkinson’s disease are widely used to elucidate the mechanisms underlying disease etiology or to investigate therapeutic approaches. Models were developed using toxins such as MPTP or 6-OHDA to specifically target dopaminergic neurons resulting in acute neuronal loss in the substantia nigra or by using viral vectors to induce the specific and gradual expression of alpha synuclein in the substantia nigra. The detection of alpha- synuclein oligomers, the presumed toxic species, in these models and others has been possible using only indirect biochemical approaches to date. Here we coinjected AAVs encoding alpha-synuclein fused to the N- or C-terminal half of VenusYFP in rat substantia nigra pars compacta and describe for the first time a novel viral vector rodent model with the unique ability to directly detect and track alpha synuclein oligomers ex vivo and in vivo. Results: Viral coinjection resulted in widespread VenusYFP signal within the nigrostriatal pathway, including cell bodies in the substantia nigra and synaptic accumulation in striatal terminals, suggestive of in vivo alpha-synuclein oligomers formation. Transduced rats showed alpha-synuclein induced dopaminergic neuron loss in the substantia nigra, the appearance of dystrophic neurites, and gliosis in the striatum. Moreover, we have applied in vivo imaging techniques in the living mouse to directly image alpha-synuclein oligomers in the cortex. Conclusion: We have developed a unique animal model that provides a tool for the Parkinson’s disease research community with which to directly detect alpha- synuclein oligomers in vivo and screen therapeutic approaches targeting alpha-synuclein oligomers

Appropriateness of Proton Pump Inhibitor Use in Hospitalized Patients: A Cross Sectional Study in a Tertiary Care Hospital in North India

Background: Proton Pump Inhibitors (PPIs) are often prescribed inappropriately among hospitalized patients and same is often continued even after their discharge from the hospital. The inappropriate use of PPIs leads to an increased risk of adverse effects, drug interaction, and unnecessary hospital expenditure for such patients. Aim of this study was to determine the appropriateness of PPIs use among hospitalized patients. Methods: A cross sectional observational study was conducted on hospitalized patients in a tertiary care hospital in Northern India. The clinical records of adult patients hospitalized during April- May 2022 were assessed for the prescribing pattern and appropriateness of PPI use as per the National Institute of Health and Care Excellence (NICE) guidelines. Results: A total of 192 patient’s records were included in this study with the mean age 57 years and 61% of the study participants were males. Overall, 72% (138) of the study participants were prescribed PPIs by intravenous route and only in 28% (54) cases an oral route was preferred. Pantoprazole was the most commonly prescribed PPI in 112 (58%) patients and it was administered by intravenous route among 87 patients (78%) and by oral route in 25 (22%) patients. PPI use was appropriate in 54% of the cases and they were most commonly prescribed for ulcer prophylaxis. This study identified higher use of PPIs was seen in low risk patients for longer duration than indicated. Conclusion: PPIs are being prescribed inappropriately among hospitalized patient unrelated to their widely accepted clinical indications and are often continued unnecessarily once patient is discharged. These results suggest the need of regular audits on use of PPIs clubbed with educational initiatives to promote rational use of PPIs among hospitalized patients

Continuum field description of crack propagation

We develop continuum field model for crack propagation in brittle amorphous solids. The model is represented by equations for elastic displacements combined with the order parameter equation which accounts for the dynamics of defects. This model captures all important phenomenology of crack propagation: crack initiation, propagation, dynamic fracture instability, sound emission, crack branching and fragmentation.Comment: 4 pages, 5 figures, submitted to Phys. Rev. Lett. Additional information can be obtained from http://gershwin.msd.anl.gov/theor