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This study identifies CDKL5, a kinase associated with neurodevelopmental disorders, as a critical regulator of protein aggregate clearance in neurons through autophagy. The researchers found that CDKL5 deficiency leads to age-dependent accumulation of protein aggregates in mouse brains due to impaired activation of a signaling pathway involving SINTBAD, TBK1, and autophagy receptors p62 and TAX1BP1. CDKL5 phosphorylates SINTBAD at Ser504, which activates TBK1 and subsequently enables the selective removal of toxic protein aggregates.
Why it matters
These findings reveal that defective protein clearance may contribute to neurological symptoms in CDKL5 deficiency disorder, a rare epileptic encephalopathy. Understanding this mechanism could open new therapeutic avenues targeting the autophagy pathway to reduce protein aggregate accumulation in affected patients and potentially other neurodegenerative conditions involving proteostasis defects.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates