Autophagy activator AA-20 engages CDK5 to promote lipophagy and improve neurodegeneration-associated phenotypes
- 1The Scripps Research Institute
Abstract
Lipophagy, the selective degradation of lipid droplets (LDs) by autophagy, has the potential to ameliorate neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD), wherein LD accumulation has been linked to the exacerbation of the proteinopathy component of neurodegeneration. Pharmacological lipophagy inducers remain scarce. We previously identified AA-20 as a novel autophagy activator that acts independently of mTORC1 inhibition, thereby providing a means of stimulating autophagy while avoiding the immunosuppressive side effects associated with direct mTORC1 inhibition. Prior work also showed that AA-20 treatment reduces PolyQ aggregate levels in several C. elegans tissues. Here, we demonstrate that AA-20 enhances LD recruitment to autophagosomes and promotes LD degradation via lysosomal acid lipase activation in murine hippocampal neuronal cells, consistent with lipophagy activation. In human Swedish Amyloid Precursor Protein mutated cerebral organoids, two weeks of AA-20 treatment normalized aberrant lipidomic profiles by selectively reducing various disease-associated lipids, while also correcting the AD-associated electrical hyperexcitability phenotype. Moreover, we identified cyclin-dependent kinase 5 (CDK5), a neuronal kinase linked to AD hyperexcitability and PD pathology, as a target of AA-20. AA-20-induced autophagy and lipid clearance in HT22 cells require CDK5. In a neuronal seeding model of -synuclein pathology, AA-20 reduced pS129--synuclein levels. Collectively, these findings indicate AA-20 can promote lipophagic clearance of LDs and mitigate multiple cellular phenotypes associated with lipidopathy and proteinopathy in neurodegenerative disease models.
Related
- From intestinal barrier sensing to glial immune programming: a barrier–immune–glia relay in microbiota-associated neurodegeneration
- Applications of OptoProfilin in Living Cells for the Imaging of Focal Adhesions and Stress-Associated Phenotypes
- SLC12A7 promotes malignant phenotypes of gastric cancer cells and is associated with Ezrin-related PI3K/AKT signaling
- SLC35D1 Is Associated with Colorectal Cancer Progression, EMT-Related Phenotypes, and Immune Infiltration
- G3BP1 reduction during cellular senescence promotes SVIL expression and selected senescence-associated phenotypes
BibTeX
@misc{tan2026autophagy,
title = {{Autophagy activator AA-20 engages CDK5 to promote lipophagy and improve neurodegeneration-associated phenotypes}},
author = {E. P. Tan and L. Ambaye and A.-L. Mahul-Mellier and Y. Zhang and P. Martinez-Botia and S. R. Labra and L. A. Massey and Z. Gao and Z. Ahmed and K. Nugroho and C. Ash and W. Ren and C. M. Cole and Y. Wu and S. Ly and J. Compher and M. Almaraz and O. Lederberg and A. Matthewson and D. Rhoades and C. A. Cuoco and D. Garza and E. T. Powers and J. A. Paulo and D. Finley and S. P. Gygi and M. Petrascheck and S. A. Lipton and M. Hansen and S. Forli and M. A. Prado and H. A. Lashuel and J. W. Kelly},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.760220},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.760220v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Autophagy activator AA-20 engages CDK5 to promote lipophagy and improve neurodegeneration-associated phenotypes
AU - E. P. Tan
AU - L. Ambaye
AU - A.-L. Mahul-Mellier
AU - Y. Zhang
AU - P. Martinez-Botia
AU - S. R. Labra
AU - L. A. Massey
AU - Z. Gao
AU - Z. Ahmed
AU - K. Nugroho
AU - C. Ash
AU - W. Ren
AU - C. M. Cole
AU - Y. Wu
AU - S. Ly
AU - J. Compher
AU - M. Almaraz
AU - O. Lederberg
AU - A. Matthewson
AU - D. Rhoades
AU - C. A. Cuoco
AU - D. Garza
AU - E. T. Powers
AU - J. A. Paulo
AU - D. Finley
AU - S. P. Gygi
AU - M. Petrascheck
AU - S. A. Lipton
AU - M. Hansen
AU - S. Forli
AU - M. A. Prado
AU - H. A. Lashuel
AU - J. W. Kelly
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.760220
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.760220v1
AB - Lipophagy, the selective degradation of lipid droplets (LDs) by autophagy, has the potential to ameliorate neurodegenerative diseases such as Parkinson's (PD) and Alzheimer's (AD), wherein LD accumulation has been linked to the exacerbation of the proteinopathy component of neurodegeneration. Pharmacological lipophagy inducers remain scarce. We previously identified AA-20 as a novel autophagy activator that acts independently of mTORC1 inhibition, thereby providing a means of stimulating autophagy while avoiding the immunosuppressive side effects associated with direct mTORC1 inhibition. Prior work also showed that AA-20 treatment reduces PolyQ aggregate levels in several C. elegans tissues. Here, we demonstrate that AA-20 enhances LD recruitment to autophagosomes and promotes LD degradation via lysosomal acid lipase activation in murine hippocampal neuronal cells, consistent with lipophagy activation. In human Swedish Amyloid Precursor Protein mutated cerebral organoids, two weeks of AA-20 treatment normalized aberrant lipidomic profiles by selectively reducing various disease-associated lipids, while also correcting the AD-associated electrical hyperexcitability phenotype. Moreover, we identified cyclin-dependent kinase 5 (CDK5), a neuronal kinase linked to AD hyperexcitability and PD pathology, as a target of AA-20. AA-20-induced autophagy and lipid clearance in HT22 cells require CDK5. In a neuronal seeding model of -synuclein pathology, AA-20 reduced pS129--synuclein levels. Collectively, these findings indicate AA-20 can promote lipophagic clearance of LDs and mitigate multiple cellular phenotypes associated with lipidopathy and proteinopathy in neurodegenerative disease models.
ER -