Proteína PRION inhibe el transporte Anoxal rápido a través de un mecanismo que involucra la Caseína Quinasa 2 (CK2).

Tesina (Grado en Ciencias Biológicas)--Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Lugar de Trabajo: Instituto de Investigación Médica Mercedes y Martín Ferreyra. INIMEC-CONICET-Universidad Nacional de Córdoba. 2018. 48 h. con Anexos; ils.; tabls.; grafs. Contiene Referencia Bibliográfica.Las enfermedades priónicas incluye un número de neuropatías progresivas que involucran cambios conformacionales de la proteína prion celular (PrPC) que puede ser esporádica, familiar o infecciosa. Evidencia patológica indica que neuronas que son afectadas con el prion muestran un patrón de degeneración de muerte hacia atrás. Sin embargo, aún no han sido identificados procesos celulares específicos por PrPC que expliquen un patrón. Resultados de biología celular en cultivos primarios de neuronas revelan una inhibición del transporte axonal rápido como un efecto tóxico del PrPC. Experimentos de biología celular y farmacológicos indican que ese efecto tóxico involucraría la activación de la caseína quinasa 2. Se encontró que la quinasa fosforila e inhibe las subunidades de cadenas livianas de una de las mayores proteínas motoras convencionales, la kinesina. Colectivamente estos datos, sugieren a CK2 como un target terapeútico novedoso para prevenir gradualmente la pérdida y conectividad neuronal que caracteriza la enfermedad de prion

Legislative History: An Act to Eliminate Funding for Primary Elections Under the Maine Clean Election Act (HP635)(LD 835)

https://digitalmaine.com/legishist120/1834/thumbnail.jp

Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly

The success of a genetic breeding program in a certain period can be assessed by the genetic gain observed. Genetic progress can be estimated from the multi environmental trials (MET) data which are routinely carried out by annual species breeding programs for the assessment of new commercial cultivars. A data set of 20 years of MET of advanced soybean lines derived from four breeding programs was used to estimate and to compare the genetic gains obtained for three soybean maturity groups (early, medium and late) in four cropping regions of the State of Rio Grande do Sul. The estimated yield gains ranged from 0.0 to 71.5 kg ha-1 year-1 (3.49% per year), depending on the maturity group and region, which suggests that the genetic breeding effort does not have a similar effect among the maturity groups or benefit the regions equally. There was no evidence of genetic progress for the early maturity group in any of the four regions, whereas gains in Regions I and IV were comparatively greater than those in Regions II and III. The objectives of the soybean breeding program in the region should be redirected. Since not all the experimental lines used to estimate genetic gains were commercially released, the reported genetics gains were achieved by the breeding programs rather than those achieved by the cropping systems

Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2

Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc. Pharmacological, biochemical and cell biological experiments further indicate this toxic effect involves casein kinase 2 (CK2) activation, providing a molecular basis for the toxic effect of PrPc on FAT. CK2 was found to phosphorylate and inhibit light chain subunits of the major motor protein conventional kinesin. Collectively, these findings suggest CK2 as a novel therapeutic target to prevent the gradual loss of neuronal connectivity that characterizes prion diseases

Data from: Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2

Prion diseases include a number of progressive neuropathies involving conformational changes in cellular prion protein (PrPc) that may be fatal sporadic, familial or infectious. Pathological evidence indicated that neurons affected in prion diseases follow a dying-back pattern of degeneration. However, specific cellular processes affected by PrPc that explain such a pattern have not yet been identified. Results from cell biological and pharmacological experiments in isolated squid axoplasm and primary cultured neurons reveal inhibition of fast axonal transport (FAT) as a novel toxic effect elicited by PrPc. Pharmacological, biochemical and cell biological experiments further indicate this toxic effect involves casein kinase 2 (CK2) activation, providing a molecular basis for the toxic effect of PrPc on FAT. CK2 was found to phosphorylate and inhibit light chain subunits of the major motor protein conventional kinesin. Collectively, these findings suggest CK2 as a novel therapeutic target to prevent the gradual loss of neuronal connectivity that characterizes prion diseases

Aromaticity at position 39 in α‐synuclein: A modulator of amyloid fibril assembly and membrane‐bound conformations

Recent studies revealed that molecular events related with the physiology and pathology of αS might be regulated by specific sequence motifs in the primary sequence of αS. The importance of individual residues in these motifs remains an important open avenue of investigation. In this work, we have addressed the structural details related to the amyloid fibril assembly and lipid-binding features of αS through the design of site-directed mutants at position 39 of the protein and their study by in vitro and in vivo assays. We demonstrated that aromaticity at position 39 of αS primary sequence influences strongly the aggregation properties and the membrane-bound conformations of the protein, molecular features that might have important repercussions for the function and dysfunction of αS. Considering that aggregation and membrane damage is an important driver of cellular toxicity in amyloid diseases, future work is needed to link our findings with studies based on toxicity and neuronal cell death

PrP induces CK2-mediated phosphorylation of kinesin light chain subunits and detachment of conventional kinesin from membrane cargoes.

<p>(<b>A-B</b>) Quantitative immunoblot analysis of kinesin-1 from two pair of sister axoplasms incubated either with control PrP-Scram or PrP_{<b>106-126</b>} peptides and (<b>C-D</b>) primary embryonic mouse cortical neurons cultured for 3 days in vitro treated for one hour. Antibody 63–90 preferentially recognizes kinesin-1 light chains (KLCs) when they are not phosphorylated by CK2 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188340#pone.0188340.ref027" target="_blank">27</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188340#pone.0188340.ref035" target="_blank">35</a>]. (<b>B and D</b>) Quantitation graph bars show that PrP_{<b>106-126</b>} decreased the immunoreactivity for 63–90 versus control PrP-Scram treated axoplasms and neurons respectively. Note a significant reduction (<b>B</b>) of immunoreactivity when neurons were treated with PrP_{<b>106-126</b>} compared to PrP-Scram; (n = 5, number of independent experiments. p = 0.0313, significance was assessed at P < 0.05). (<b>D</b>) Significant reduction of 63–90 immunoreactivity in axoplasms incubated with PrP_{<b>106-126</b>} compared to control PrP-Scram, (n = 3; number of independent experiments. p = 0.0355, significance was assessed at P < 0.05). (<b>E</b>) Vesicles purified from sister axoplasms by vesicle flotation assays perfused with control PrP-Scram and PrP_{<b>106-126</b>} synthetic peptide were assayed by Western blot for KHC and TrkB. TrkB was used as membrane protein marker and for loading control. (<b>F</b>) Quantitation graph bars shows a significant reduction of kinesin-1 association to purified vesicles in PrP_{<b>106-126</b>} incubated extruded axoplasms compared to control PrP-Scram treated axoplasms, (n = 3, number of independent experiments; significance was assessed at P < 0.05). Taken together, these experiments suggest that PrP_{<b>106-126</b>} increases the intracellular activity of CK2, which in turn results in KLCs phosphorylation and kinesin-1 release from its cargo vesicles.</p

Supplementary Figure. 3 The CK2 pharmacological inhibitor DMAT does not interfere with FAT.

Supplementary Figure. 3 The CK2 pharmacological inhibitor DMAT does not interfere with FAT

Figure 2. Prion inhibits fast axonal transport of mitochondria in primary hippocampal cultured neurons.

Figure 2. Prion inhibits fast axonal transport of mitochondria in primary hippocampal cultured neurons