Medicine and Health Sciences Commons^™

Two C-Terminal Sequence Variations Determine Differential Neurotoxicity Between Human And Mouse Α-Synuclein, Natalie Landeck, Katherine E. Strathearn, Daniel Ysselstein, Kerstin Buck, Sayan Dutta, Siddhartha Banerjee, Zhengjian Lv, John D. Hulleman, Jagadish Hindupur, Li-Kai Lin, Sonal Padalkar, Lia A. Stanciu, Yuri L. Lyubchenko, Deniz Kirik, Jean-Christophe Rochet

Journal Articles: Pharmaceutical Sciences

BACKGROUND: α-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson's disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here, we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models, as well as their biochemical properties relevant to aSyn pathobiology.

METHODS: Primary midbrain cultures transduced with aSyn-encoding adenoviruses were analyzed immunocytochemically to determine relative dopaminergic neuron viability. …

Interaction Of Aβ42 With Membranes Triggers The Self-Assembly Into Oligomers, Siddhartha Banerjee, Mohtadin Hashemi, Karen Zagorski, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

The self-assembly of amyloid β (Aβ) proteins into oligomers is the major pathogenic event leading to Alzheimer's disease (AD). Typical in vitro experiments require high protein concentrations, whereas the physiological concentration of Aβ is in the picomolar to low nanomolar range. This complicates the translation of results obtained in vitro to understanding the aggregation process in vivo. Here, we demonstrate that Aβ42 self-assembles into aggregates on membrane bilayers at low nanomolar concentrations - a pathway in which the membrane plays the role of a catalyst. Additionally, physiological ionic conditions (150 mM NaCl) significantly enhance on-membrane aggregation, leading to the rapid …

Nanoscale Interaction Of Recg With Mobile Fork Dna, Zhiqiang Sun, Yaqing Wang, Piero R. Bianco, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

RecG DNA helicase is a guardian of the bacterial genome where it dominates stalled DNA replication fork rescue. The single-stranded DNA binding protein (SSB) is involved in this process and promotes the binding of RecG to stalled replication forks. Atomic force microscopy (AFM) was used to investigate the interaction of RecG and SSB on a mobile fork substrate capable of being regressed. In the absence of proteins, the fork undergoes spontaneous dynamics between two states, defined by the length of the DNA complementarity at the fork. The binding of SSB does not affect these dynamics as it binds to single-stranded …

Afm Probing Of Amyloid-Beta 42 Dimers And Trimers, Sibaprasad Maity, Yuri L. Lyubchenko

Journal Articles: Pharmaceutical Sciences

Elucidating the molecular mechanisms in the development of such a devastating neurodegenerative disorder as Alzheimer's disease (AD) is currently one of the major challenges of molecular medicine. Evidence strongly suggests that the development of AD is due to the accumulation of amyloid β (Aβ) oligomers; therefore, understanding the molecular mechanisms defining the conversion of physiologically important monomers of Aβ proteins into neurotoxic oligomeric species is the key for the development of treatments and preventions of AD. However, these oligomers are unstable and unavailable for structural, physical, and chemical studies. We have recently developed a novel flexible nano array (FNA)-oligomer scaffold …

Neuronal-Derived Extracellular Vesicles Are Enriched In The Brain And Serum Of Hiv-1 Transgenic Rats, Raghubendra S. Dagur, Ke Liao, Susmita Sil, Fang Niu, Zhiqiang Sun, Yuri L. Lyubchenko, Eric S. Peebles, Guoku Hu, Shilpa Buch

Journal Articles: Pharmaceutical Sciences

Despite the efficacy of combination antiretroviral therapy (ART) in controlling human immunodeficiency virus (HIV-1) replication, cytotoxic viral proteins such as HIV-1 transactivator of transcription (Tat) persist in tissues such as the brain. Although HIV-1 does not infect neuronal cells, it is susceptible to viral Tat protein-mediated toxicity, leading to neuroinflammation that underlies HIV-associated neurocognitive disorders (HAND). Given the role of extracellular vesicles (EVs) in both cellular homoeostasis and under pathological conditions, we sought to investigate the alterations in the quantity of neuronal-derived EVs in the brain–as defined by the presence of cell adhesion molecule L1 (L1CAM) and to evaluate the …

The Current State Of Drug Repurposing And Rare Diseases: An Interview With Paul Trippier, Paul C. Trippier

Journal Articles: Pharmaceutical Sciences

Paul Tripper is an Associate Professor of Medicinal Chemistry at the University of Nebraska Medical Center (UNMC, NE, USA) and an Editorial Board member of Future Drug Discovery. Here, he speaks to Managing Editor Francesca Lake about drug repurposing, focusing on the key challenges, its application to rare diseases and what we can look forward to in the future.

Exogenous Flupirtine As Potential Treatment For Cln3 Disease, Katia Maalouf, Joelle Makoukji, Sara Saab, Nadine J. Makhoul, Angelica V. Carmona, Nihar Kinarivala, Noël Ghanem, Paul C. Trippier, Rose-Mary Boustany

Journal Articles: Pharmaceutical Sciences

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3^Δex7/8 mice. WT/Cln3^Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in …