Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression
| Autor: | Sujatha M. Gopalakrishnan, Xiaoying Chen, Diana Donnelly-Roberts, Navasona Krishnan, Eric G. Mohler, David M. Holtzman |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Phenotypic screening Disease Bioinformatics 01 natural sciences Biochemistry Small Molecule Libraries 03 medical and health sciences Alzheimer Disease Medicine Dementia Humans Cognitive decline RNA Small Interfering 010405 organic chemistry business.industry Treatment options Reproducibility of Results General Medicine medicine.disease Small molecule 0104 chemical sciences 030104 developmental biology Expression (architecture) Receptors LDL Gene Knockdown Techniques LDL receptor Molecular Medicine business |
| Zdroj: | ACS chemical biology. 15(12) |
| ISSN: | 1554-8937 |
| Popis: | Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of dementia. Hence, more effective therapeutic strategies are needed to combat this devastating disease. The low-density lipoprotein receptor has been shown to modulate the neuronal metabolism of cholesterol and apolipoprotein E, a major genetic risk factor for AD. LDLR overexpression in mice has been shown to increase amyloid-β clearance and reduce amyloid deposition. We conducted a phenotypic screen to identify novel signaling pathways and targets that regulate LDLR expression in glial cells using an annotated compound library of approximately 29 000 compounds. The screen identified novel targets such as polo like kinase 1 (PLK1), activin receptor like kinase 5 (ALK5), and serotonin transporter (SERT). We used genetic, chemical biology and pathway analysis to confirm the target hypothesis. This work highlights that phenotypic screening is a promising strategy to identify novel mechanisms and targets for therapeutic intervention of complex neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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