Translational Neurodegeneration | SIK2 promotes autophagosome-lysosome fusion through phosphorylation of GABARAPL2 and alleviates neurodegeneration in Alzheimer's disease models

This study reveals the protective role of SIK2 in Alzheimer's disease (AD) models by phosphorylating GABARAPL2 protein to promote autophagosome-lysosome fusion, thereby reducing Aβ deposition and improving cognitive function. The research not only identifies the SIK2-GABARAPL2 signaling axis as a novel mechanism in autophagy regulation but also provides potential therapeutic targets for AD treatment.

 

Literature Overview
The article titled 'SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome–lysosome fusion and rescues neurodegeneration in an Alzheimer’s disease model', published in the journal 'Translational Neurodegeneration', reviews and summarizes the research findings that SIK2 (salt-inducible kinase 2) enhances autophagosome-lysosome fusion through phosphorylation of GABARAPL2 (GABA receptor-associated protein-like 2), thus reducing Aβ deposition and improving synaptic plasticity and cognitive function in AD models.

Background Knowledge
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ deposition and synaptic dysfunction. The autophagy-lysosome system plays a crucial role in protein homeostasis and neuronal health, and its dysfunction has been widely linked to AD pathology. GABARAPL2, a member of the ATG8 family, is a key regulator of autophagosome maturation and lysosomal fusion, with its phosphorylation status affecting autophagic efficiency. SIK2, a member of the AMPK family, participates in metabolic regulation and neuroprotection, though its specific role in AD remains unclear. This study aims to explore whether SIK2 regulates autophagosome-lysosome fusion through phosphorylation of GABARAPL2, thereby influencing AD progression. The research team systematically evaluated the role of the SIK2-GABARAPL2 signaling axis in AD using bioinformatics, immunohistochemistry, gene knockout and overexpression mouse models, combined with behavioral, electrophysiological, and ultrastructural analyses.

 

 

Research Methods and Experiments
The research team first evaluated the expression and age-related changes of SIK2 in hippocampal tissues from AD patients and 5 × FAD mice, finding that SIK2 was significantly downregulated with age in AD models. Subsequently, using AAV-mediated SIK2 knockdown and overexpression combined with Morris water maze testing, LTP recording, and transmission electron microscopy, the effects of SIK2 on cognitive function and synaptic plasticity were assessed. Further, LC3B/p62 turnover assays, mRFP-GFP-LC3 tandem fluorescence detection, and electron microscopy were employed to monitor autophagosome-lysosome fusion. Immunoprecipitation, GST-pull down, phosphoproteomic, and site-directed mutagenesis techniques were used to investigate the interaction between SIK2 and GABARAPL2 and the functional significance of the phosphorylation site (Ser72). Finally, hippocampal injection of phospho-mimetic (S72E) and non-phosphorylatable (S72A) GABARAPL2 mutants was conducted to evaluate their impact on AD pathology and behavior.

Key Conclusions and Perspectives

• SIK2 is significantly downregulated in hippocampal neurons of AD patients and 5 × FAD mice with aging, and its expression level is positively correlated with spatial memory deficits.
• Knocking down SIK2 exacerbates cognitive impairment, Aβ deposition, and synaptic pathology in mice, whereas SIK2 overexpression significantly ameliorates these phenotypes, including restoring LTP, reducing Aβ plaques, and repairing synaptic ultrastructure.
• SIK2 promotes autophagosome-lysosome fusion by phosphorylating GABARAPL2 at Ser72, a modification critical for Aβ clearance and synaptic maintenance.
• The phospho-mimetic GABARAPL2-S72E mutation effectively restores autophagic function, reduces Aβ deposition, and improves cognitive behavior in 5 × FAD mice, while the non-phosphorylatable S72A mutation lacks protective effects.

Research Significance and Prospects
This study is the first to reveal that the SIK2-GABARAPL2 signaling axis exerts neuroprotection in AD models by regulating autophagosome-lysosome fusion, providing a new molecular mechanism for AD-related autophagy dysfunction. Future studies should further investigate the regulatory mechanisms of this signaling axis and develop drugs targeting SIK2 or GABARAPL2 phosphorylation to enhance autophagy and improve AD pathology. Additionally, it is worth exploring whether this mechanism is broadly relevant to other neurodegenerative diseases, such as Parkinson’s and Huntington’s diseases.

 

 

Conclusion
This study systematically demonstrates that SIK2 promotes autophagosome-lysosome fusion through phosphorylation of GABARAPL2, thereby reducing Aβ deposition and improving cognitive and synaptic function in AD model mice. It not only establishes the SIK2-GABARAPL2 axis as a novel target for autophagy regulation but also provides potential therapeutic strategies for AD treatment. The neuroprotective effects of the phospho-mimetic S72E mutation suggest that enhancing GABARAPL2 phosphorylation may represent a new intervention approach for autophagy-deficient neurodegenerative diseases. Future studies should further explore the role of this signaling axis in other neurodegenerative diseases and assess its feasibility as a drug target.

 

Xiaoman Dai, Ziling Ye, Chen Wang, Jing Zhang, and Xiaochun Chen. SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome–lysosome fusion and rescues neurodegeneration in an Alzheimer’s disease model. Translational Neurodegeneration.