scholarly journals Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

2020 ◽  
Author(s):  
Fleur Ferguson
Keyword(s):  
Frontotemporal Dementia ◽  
Neuronal Cell ◽  
Dementia Patient ◽  
Cell Models

scholarly journals Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
M Catarina Silva ◽  
Fleur M Ferguson ◽  
Quan Cai ◽  
Katherine A Donovan ◽  
Ghata Nandi ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Ubiquitin Ligase ◽  
Neuronal Cell ◽  
Dementia Patient ◽  
Protein Accumulation ◽  
Cell Models ◽  
Stress Vulnerability ◽  
Bifunctional Molecule ◽  
Positron Emission ◽  
Current Therapies

Tauopathies are neurodegenerative diseases characterized by aberrant forms of tau protein accumulation leading to neuronal death in focal brain areas. Positron emission tomography (PET) tracers that bind to pathological tau are used in diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET-probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01–175 was designed to engage both tau and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, to trigger tau ubiquitination and proteasomal degradation. QC-01–175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, with minimal effect on tau from neurons of healthy controls, indicating specificity for disease-relevant forms. QC-01–175 also rescued stress vulnerability in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.

scholarly journals Author response: Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

2019 ◽  
Author(s):  
M Catarina Silva ◽  
Fleur M Ferguson ◽  
Quan Cai ◽  
Katherine A Donovan ◽  
Ghata Nandi ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Neuronal Cell ◽  
Author Response ◽  
Dementia Patient ◽  
Cell Models

scholarly journals The Novel Alpha-2 Adrenoceptor Inhibitor Beditin Reduces Cytotoxicity and Huntingtin Aggregates in Cell Models of Huntington’s Disease

2021 ◽  
Vol 14 (3) ◽  
pp. 257
Author(s):  
Elisabeth Singer ◽  
Lilit Hunanyan ◽  
Magda M. Melkonyan ◽  
Jonasz J. Weber ◽  
Lusine Danielyan ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Cell Model ◽  
Resonance Energy Transfer ◽  
Neuronal Cell ◽  
Resonance Energy ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Cell Models

Huntington’s disease (HD) is a monogenetic neurodegenerative disorder characterized by the accumulation of polyglutamine-expanded huntingtin (mHTT). There is currently no cure, and therefore disease-slowing remedies are sought to alleviate symptoms of the multifaceted disorder. Encouraging findings in Alzheimer’s and Parkinson’s disease on alpha-2 adrenoceptor (α2-AR) inhibition have shown neuroprotective and aggregation-reducing effects in cell and animal models. Here, we analyzed the effect of beditin, a novel α2- adrenoceptor (AR) antagonist, on cell viability and mHTT protein levels in cell models of HD using Western blot, time-resolved Foerster resonance energy transfer (TR-FRET), lactate dehydrogenase (LDH) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) cytotoxicity assays. Beditin decreases cytotoxicity, as measured by TUNEL staining and LDH release, in a neuronal progenitor cell model (STHdh cells) of HD and decreases the aggregation propensity of HTT exon 1 fragments in an overexpression model using human embryonic kidney (HEK) 293T cells. α2-AR is a promising therapeutic target for further characterization in HD models. Our data allow us to suggest beditin as a valuable candidate for the pharmaceutical manipulation of α2-AR, as it is capable of modulating neuronal cell survival and the level of mHTT.

scholarly journals Distribution of Particles in Human Stem Cell-Derived 3D Neuronal Cell Models: Effect of Particle Size, Charge, and Density

2020 ◽  
Vol 21 (8) ◽  
pp. 3186-3196
Author(s):  
Ewa Czuba-Wojnilowicz ◽  
Sara Miellet ◽  
Agata Glab ◽  
Serena Viventi ◽  
Francesca Cavalieri ◽  
...  
Keyword(s):  
Particle Size ◽  
Stem Cell ◽  
Neuronal Cell ◽  
Human Stem Cell ◽  
Cell Models ◽  
Effect Of Particle Size

Immortalized neurons for the study of hypothalamic function

2011 ◽  
Vol 300 (5) ◽  
pp. R1030-R1052 ◽  
Author(s):  
Prasad S. Dalvi ◽  
Anaies Nazarians-Armavil ◽  
Stephanie Tung ◽  
Denise D. Belsham
Keyword(s):  
Neuronal Cell ◽  
Glucose Sensing ◽  
T Antigen ◽  
Molecular Techniques ◽  
Cell Models ◽  
Hypothalamic Neurons ◽  
In Vivo Models ◽  
Wide Range ◽  
Hypothalamic Function

The hypothalamus is a vital part of the central nervous system: it harbors control systems implicated in regulation of a wide range of homeostatic processes, including energy balance and reproduction. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of a multitude of unique neuronal cell types that express a number of neuromodulators, including hormones, classical neurotransmitters, and specific neuropeptides that play a critical role in mediating hypothalamic function. However, neuropeptide and receptor gene expression, second messenger activation, and electrophysiological and secretory properties of these hypothalamic neurons are not yet fully defined, primarily because the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus make such studies challenging to perform in vivo. To circumvent this problem, our research group recently generated embryonic- and adult-derived hypothalamic neuronal cell models by utilizing the novel molecular techniques of ciliary neurotrophic factor-induced neurogenesis and SV40 T antigen transfer to primary hypothalamic neuronal cell cultures. Significant research with these cell lines has demonstrated their value as a potential tool for use in molecular genetic analysis of hypothalamic neuronal function. Insights gained from hypothalamic immortalized cells used in conjunction with in vivo models will enhance our understanding of hypothalamic functions such as neurogenesis, neuronal plasticity, glucose sensing, energy homeostasis, circadian rhythms, and reproduction. This review discusses the generation and use of hypothalamic cell models to study mechanisms underlying the function of individual hypothalamic neurons and to gain a more complete understanding of the overall physiology of the hypothalamus.

scholarly journals A synthetic analog of verbenachalcone potentiates NGF-induced neurite outgrowth and enhances cell survival in neuronal cell models

2009 ◽  
Vol 459 (3) ◽  
pp. 157-161 ◽  
Author(s):  
Ceiléssia M. Clement ◽  
Srinivasa R. Dandepally ◽  
Alfred L. Williams ◽  
Gordon C. Ibeanu
Keyword(s):  
Cell Survival ◽  
Neurite Outgrowth ◽  
Neuronal Cell ◽  
Synthetic Analog ◽  
Cell Models
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