VCP/p97 mediates nuclear targeting of non-ER-imported prion protein to maintain proteostasis.

Mistargeting of secretory proteins in the cytosol can trigger their aggregation and subsequent proteostasis decline. We have identified a VCP/p97-dependent pathway that directs non-ER-imported prion protein (PrP) into the nucleus to prevent the formation of toxic aggregates in the cytosol. Upon impaired translocation into the ER, PrP interacts with VCP/p97, which facilitates nuclear import mediated by importin-ß. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import are independent of ubiquitination. In vitro experiments revealed that VCP/p97 binds non-ubiquitinated PrP and prevents its aggregation. Inhibiting binding of PrP to VCP/p97, or transient proteotoxic stress, promotes the formation of self-perpetuating and partially proteinase resistant PrP aggregates in the cytosol, which compromised cellular proteostasis and disrupted further nuclear targeting of PrP. In the nucleus, RNAs keep PrP in a soluble and non-toxic conformation. Our study revealed a novel ubiquitin-independent role of VCP/p97 in the nuclear targeting of non-imported secretory proteins and highlights the impact of the chemical milieu in triggering protein misfolding.

Cross-seeding by prion protein inactivates TDP-43.

A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models and patients' brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43). Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt-Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.

COVID-19 pandemic: a health challenge for commoners during the first unlock phase in India.

Aim: COVID-19, the disease caused by the novel coronavirus, is now a worldwide pandemic. This disease has become a reason for disturbance and concern. India, as a densely populated country, took initiative after the pandemic was declared. The objective of this study was to determine the mortality and recovery rates at 30 days from the first unlock phase after five phases of lockdown. The the number of infected people has continually increased, and currently, this pandemic continues to present challenges to public health. Subject and methods: Statistical analysis was used to calculate the mortality rate, ratio between active and death cases, active cases and recovered cases, recovered and death cases in India during the first 30 days of the unlock phase. Results: The relationship between the new cases, deaths and recovered cases, shows that the new and recovered cases increased progressively. From the scatter plot of daily deaths and new cases, the R2 value is 0.0047. That means the death ratio is low against the new cases. Also, if we look at another scatter plot, the ratio between new cases and recovery rate shows the R2 value is 0.8015. That means the recovery rate was very high during the study period in India. The R2 value of daily recovery and death is 0.0072. India faced a huge number of new coronavirus cases and increased death rate every day during the first unlock phase. Conclusion: There was not the same condition as in the preliminary stage. The affected graphs progressively increased, and the government is fighting to control this deadly infection. Central and state governments are working together to combat this pandemic.

Statistical data analysis of risk factor associated with mortality rate by COVID-19 pandemic in India.

The coronavirus is an infection caused by severe acute respiratory syndrome (SARS) coronavirus, known as SARS-CoV-2. It was first determined in Wuhan, China in December 2019. WHO named this virus as COVID-19. Virologist says that COVID-19 is similar to SARS and MARS virus. This deadly disease affected worldwide economically, hammering people lifestyle and also the environmental condition. After a few months, there is no vaccine to build the barricade between this virus and life. Many countries have tried to improve the methodology to control the disease and also the actual vaccine for coronavirus but not yet successful. Rapid testing, quarantine and social distancing slow down the social and economic movement. Although India, as one of the largest populated country, takes some respectable initiative after the pandemic of the novel coronavirus. According to WHO 24th May 2020 report, total 131,868 confirmed cases and killed over 3867 people by this COVID-19 pandemic. Indian government takes the initiative like janta curfew, lockdown all over the country. The main focus or aim of this study is to find the mortality rate and the recovered people at the fourth phase of lockdown, but the infected graph is daily increased in India. In the relation between active cases and the death cases, the R 2 value is 0.8754. The relation between active cases and the recoveries, the R 2 value is 0.9246. In between 116 days, the mortality rate is less in before lockdown (0.129%) and third phase lockdown is facing a huge mortality rate (43.496%).