CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates
- 1UT Southwestern Medical Center, Dallas, Texas
Abstract
The clearance of unwanted protein aggregates is essential for maintaining proteostasis and cellular function, particularly in long-lived cells such as neurons, yet the signaling pathways that activate selective autophagy of protein aggregates remain incompletely understood. Here, we identify the neurodevelopmental kinase CDKL5 as an upstream regulator of a signaling pathway involving the TBK1 adaptor SINTBAD and the selective autophagy receptors p62 and TAX1BP1. CDKL5-deficient mice show age-dependent accumulation of detergent-insoluble protein aggregates in the brain, accompanied by impaired TAX1BP1 recruitment and reduced p62 Ser405 phosphorylation. In cultured cells and primary cortical neurons, loss of CDKL5 delays clearance of puromycin- and proteasome-inhibitor-induced aggregates in a manner dependent on CDKL5 kinase activity. Mechanistically, CDKL5 kinase activity is required for SINTBAD Ser504 phosphorylation, a SINTBAD modification that promotes TBK1 activation, resulting in p62 Ser403/405 phosphorylation and TAX1BP1-dependent aggregate clearance. Phosphomimetic SINTBAD rescues these responses in CDKL5-deficient cells. These findings define a CDKL5/SINTBAD/TBK1 signaling axis that couples proteotoxic stress to activation of selective autophagy receptors and identify impaired proteostasis as a previously unrecognized consequence of CDKL5 deficiency.
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BibTeX
@misc{zou2026cdkl5,
title = {{CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates}},
author = {Z. Zou and B. Kahn and S. Sebti and J. Lucavs and G. Rivera-Cancel and J. Thinwa},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.13.751248},
url = {https://www.biorxiv.org/content/10.64898/2026.09.13.751248v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates
AU - Z. Zou
AU - B. Kahn
AU - S. Sebti
AU - J. Lucavs
AU - G. Rivera-Cancel
AU - J. Thinwa
PY - 2026
DA - 2026/09/13
PB - bioRxiv
DO - 10.64898/2026.09.13.751248
UR - https://www.biorxiv.org/content/10.64898/2026.09.13.751248v1
AB - The clearance of unwanted protein aggregates is essential for maintaining proteostasis and cellular function, particularly in long-lived cells such as neurons, yet the signaling pathways that activate selective autophagy of protein aggregates remain incompletely understood. Here, we identify the neurodevelopmental kinase CDKL5 as an upstream regulator of a signaling pathway involving the TBK1 adaptor SINTBAD and the selective autophagy receptors p62 and TAX1BP1. CDKL5-deficient mice show age-dependent accumulation of detergent-insoluble protein aggregates in the brain, accompanied by impaired TAX1BP1 recruitment and reduced p62 Ser405 phosphorylation. In cultured cells and primary cortical neurons, loss of CDKL5 delays clearance of puromycin- and proteasome-inhibitor-induced aggregates in a manner dependent on CDKL5 kinase activity. Mechanistically, CDKL5 kinase activity is required for SINTBAD Ser504 phosphorylation, a SINTBAD modification that promotes TBK1 activation, resulting in p62 Ser403/405 phosphorylation and TAX1BP1-dependent aggregate clearance. Phosphomimetic SINTBAD rescues these responses in CDKL5-deficient cells. These findings define a CDKL5/SINTBAD/TBK1 signaling axis that couples proteotoxic stress to activation of selective autophagy receptors and identify impaired proteostasis as a previously unrecognized consequence of CDKL5 deficiency.
ER -