A5090589412- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Alzheimer's disease research and treatments
- Phenothiazines and Benzothiazines Synthesis and Activities
- Amyotrophic Lateral Sclerosis Research
- Pharmacological Receptor Mechanisms and Effects
- Computational Drug Discovery Methods
- Autophagy in Disease and Therapy
- Synthesis of heterocyclic compounds
- Cholinesterase and Neurodegenerative Diseases
- RNA regulation and disease
- Biochemical Acid Research Studies
- Lysosomal Storage Disorders Research
- Amino Acid Enzymes and Metabolism
- Endoplasmic Reticulum Stress and Disease
The Ohio State University
2024
Boston University
2018-2024
University of Maryland, Baltimore
2016-2020
Significance Animal models of human diseases provide important tools for mechanistic and preclinical investigations. Mutations in several genes cause ALS. One such gene is ubiquilin 2 ( UBQLN2 ), mutations which dominant inheritance ALS with frontotemporal dementia (ALS–FTD). Several rodent carrying have been described, but none develop motor neuron disease. We describe two transgenic (Tg) mouse ALS–FTD different mutations. Both cognitive deficits, classic TAR-DNA binding protein 43 (TDP-43)...
Significance Mutations in UBQLN2 cause amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). regulates proteostasis by clearing misfolded proteins from cells through the proteasome and autophagy degradation pathways. Here, we report on defects that results knockout or expression of WT ALS/FTD mutant mice. We show loss reduces ATP6v1g1, a critical subunit ATPase pump vacuolar acidification is required for maturation autophagosomes. but not can rescue defect. Furthermore, bind...
Synaptic degeneration is one of the earliest pathological correlates prion disease, and it a major determinant progression clinical symptoms. However, cellular molecular mechanisms underlying synaptotoxicity are poorly understood. Previously, we described an experimental system in which treatment cultured hippocampal neurons with purified PrPSc, infectious form protein, induces rapid retraction dendritic spines, effect that entirely dependent on expression endogenous PrPC by target neurons....
Prion diseases are invariably fatal neurodegenerative of humans and other animals for which there no effective treatment options. Previous work from our laboratory identified phenethylpiperidines as a novel class anti-prion compounds. While working to identify the molecular target(s) these molecules, we unexpectedly discovered ten antiprion compounds based on their known ability bind sigma receptors, σ1R σ2R, currently being tested therapeutic or diagnostic targets cancer neuropsychiatric...
We recently described a p38 MAP kinase-dependent synaptotoxic signaling pathway that is activated by prions (Fang et al. 2018, PLoS Pathog. 14:e1007283). Although there evidence MAPK also plays role in the toxicity of Aβ oligomers (Birnbaum al, 2015, Cell Death Dis, 18;6:e1791), we reported previously non-selective chemical inhibitor all four isoforms (SB239063) did not prevent dendritic spine retraction caused synthetic ADDLs 2018). To further explore relationship between activation and...
Abstract Prion diseases are invariably fatal neurodegenerative of humans and other animals for which there no treatment options. Previous work from our laboratory identified phenethyl piperidines as novel class anti-prion compounds. While working to identify the molecular target(s) these molecules, we unexpectedly discovered ten compounds based on their known ability bind sigma receptors, σ 1 R 2 R, currently being tested therapeutic or diagnostic targets cancer neuropsychiatric disorders....
Summary The most common subtype of genetic prion disease is caused by the E200K mutation protein. We have obtained samples from 22 members a multi-generational Israeli family harboring this mutation, and generated library induced pluripotent stem cells (iPSCs) representing nine carriers four non-carriers. Whole-exome sequencing was performed on all individuals. A comparison neurons derived iPSCs to those non-carriers revealed presence several disease-relevant phenotypes. Neurons were found...