TY - JOUR
T1 - Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression
AU - Krishnan, Navasona
AU - Chen, Xiaoying
AU - Donnelly-Roberts, Diana
AU - Mohler, Eric G.
AU - Holtzman, David M.
AU - Gopalakrishnan, Sujatha M.
N1 - Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/12/18
Y1 - 2020/12/18
N2 - 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 29000 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.
AB - 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 29000 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.
UR - http://www.scopus.com/inward/record.url?scp=85097785829&partnerID=8YFLogxK
U2 - 10.1021/acschembio.0c00851
DO - 10.1021/acschembio.0c00851
M3 - Article
C2 - 33270420
AN - SCOPUS:85097785829
SN - 1554-8929
VL - 15
SP - 3262
EP - 3274
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 12
ER -