Biology subjects

Kraemer, B. R.

Publications and source records attributed to Kraemer, B. R..

4 recordsLinked to original sources

bioRxiv2024

LM11a-31 Inhibits p75 Neurotrophin Receptor (p75NTR) Cleavage and is Neuroprotective in a Cell Culture Model of Parkinson's Disease.

The p75 Neurotrophin Receptor (p75NTR) is a multifunctional transmembrane protein that mediates neuronal responses to pathological conditions in specific regions of the nervous system. In many biological contexts, p75NTR signaling is initiated through sequential cleavage of the receptor by - and {gamma}-secretases, which releases receptor fragments for downstream signaling. Our previous work demonstrated that proteolytic processing of p75NTR in this manner is stimulated by oxidative stress in Lund Human Mesencephalic (LUHMES) cells, a dopaminergic neuronal cell line derived from human mesencephalic tissue. Considering the vulnerability of dopaminergic neurons in the ventral mesencephalon to oxidative stress and neurodegeneration associated with Parkinsons disease (PD), we investigated the role of this signaling cascade in neurodegeneration and explored cellular processes that govern oxidative stress-induced p75NTR signaling. In the present study, we provide evidence that oxidative stress induces cleavage of p75NTR by promoting c-Jun N-terminal Kinase (JNK)-dependent internalization of p75NTR from the cell surface. This activation of p75NTR signaling is counteracted by tropomyosin-related kinase (Trk) receptor signaling; however, oxidative stress leads to Trk receptor downregulation, thereby enhancing p75NTR processing. Importantly, we demonstrate that this pathway can be inhibited by LM11a-31, a small molecule modulator of p75NTR, thereby conferring protection against neurodegeneration. Treatment with LM11a-31 significantly reduced p75NTR cleavage and neuronal death associated with oxidative stress. These findings reveal novel mechanisms underlying activation of p75NTR in response to oxidative stress, underscore a key role for p75NTR in dopaminergic neurodegeneration, and highlight p75NTR as a potential therapeutic target for reducing neurodegeneration in PD.

neuroscience↗

bioRxiv2021

Increased elastase sensitivity and decreased intramolecular interactions in the more transmissible SARS-CoV-2 variants' spike protein

Two SARS-CoV-2 variants showing increased transmissibility relative to the Wuhan virus have recently been identified. Although neither variant causes more severe illness or increased risk of death, the faster spread of the virus is a major threat. Using computational tools, we found that the new SARS-CoV-2 variants may acquire an increased transmissibility by increasing the propensity of its spike protein to expose the receptor binding domain. This information leads to the identification of potential treatments to avert the imminent threat of these more transmittable SARS-CoV-2 variants. TeaserThe more infective SARS-CoV-2 variants may expose its Achilles Heel - an opportunity to reduce their spreading.

molecular biology↗

bioRxiv2021

Natural variants in SARS-CoV-2 S protein pinpoint structural and functional hotspots; implications for prophylaxis strategies

In December 2019, a novel coronavirus, termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of pneumonia with severe respiratory distress and outbreaks in Wuhan, China. The rapid and global spread of SARS-CoV-2 resulted in the coronavirus 2019 (COVID-19) pandemic. Earlier during the pandemic, there were limited genetic viral variations. As millions of people became infected, multiple single amino acid substitutions emerged. Many of these substitutions have no consequences. However, some of the new variants show a greater infection rate, more severe disease, and reduced sensitivity to current prophylaxes and treatments. Of particular importance in SARS-CoV-2 transmission are mutations that occur in the Spike (S) protein, the protein on the viral outer envelope that binds to the human angiotensin-converting enzyme receptor (hACE2). Here, we conducted a comprehensive analysis of 441,168 individual virus sequences isolated from humans throughout the world. From the individual sequences, we identified 3,540 unique amino acid substitutions in the S protein. Analysis of these different variants in the S protein pinpointed important functional and structural sites in the protein. This information may guide the development of effective vaccines and therapeutics to help arrest the spread of the COVID-19 pandemic.

molecular biology↗

bioRxiv2020

Paired SARS CoV-2 Spike Protein Mutations Observed During Ongoing SARS-CoV-2 Viral Transfer from Humans to Minks and Back to Humans

A mutation analysis of SARS-CoV-2 genomes collected around the world sorted by sequence, date, geographic location, and species has revealed a large number of variants from the initial reference sequence in Wuhan. This analysis also reveals that humans infected with SARS-CoV-2 have infected mink populations in the Netherlands, Denmark, United States, and Canada. In these animals, a small set of mutations in the spike protein receptor binding domain (RBD), often occurring in specific combinations, has transferred back into humans. The viral genomic mutations in minks observed in the Netherlands and Denmark show the potential for new mutations on the SARS-CoV-2 spike protein RBD to be introduced into humans by zoonotic transfer. Our data suggests that close attention to viral transfer from humans to farm animals and pets will be required to prevent build-up of a viral reservoir for potential future zoonotic transfer.

genetics↗