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, where it promotes autophagosome-lysosome fusion through phosphorylation of the GABARAPL2 protein, 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 findings that SIK2 (salt-inducible kinase 2) enhances autophagosome-lysosome fusion through phosphorylation of GABARAPL2 (GABA receptor-associated protein-like 2) in Alzheimer's disease models, thereby reducing Aβ deposition and improving synaptic plasticity and cognitive function.

Background Knowledge
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by Aβ deposition and synaptic dysfunction. The autophagy-lysosome system plays a critical role in protein homeostasis and neuronal health, with its dysfunction being widely linked to AD pathology. GABARAPL2, a member of the ATG8 family, is a key regulator of autophagosome maturation and lysosome fusion, with its phosphorylation status affecting autophagy efficiency. SIK2, a member of the AMPK family, participates in metabolic and neuroprotective processes but its specific role in AD remains unclear. This study aims to explore whether SIK2 regulates autophagosome-lysosome fusion through phosphorylation of GABARAPL2, thus 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 assessed the expression and age-related changes of SIK2 in the hippocampal tissues of 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, they evaluated the impact of SIK2 on cognitive function and synaptic plasticity. Further, they examined autophagosome-lysosome fusion using LC3B/p62 turnover assays, mRFP-GFP-LC3 tandem fluorescence detection, and electron microscopy. Immunoprecipitation, GST-pull down, phosphoproteomic analysis, and site-directed mutagenesis were employed to investigate the interaction between SIK2 and GABARAPL2, as well as the functional role of the phosphorylation site (Ser72). Finally, the effects of the phosphorylation-mimicking (S72E) and non-phosphorylatable (S72A) GABARAPL2 mutants on AD pathology and behavior were evaluated through hippocampal injections.

Key Conclusions and Perspectives

• SIK2 is significantly downregulated in hippocampal neurons of AD patients and 5 × FAD mice with age, and its expression levels are positively correlated with spatial memory deficits.
• SIK2 knockdown exacerbates cognitive impairments, Aβ deposition, and synaptic pathology in mice, while SIK2 overexpression significantly improves these phenotypes, including restoring LTP, reducing amyloid 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 mutant effectively restores autophagy function, reduces Aβ deposition, and improves cognitive behavior in 5 × FAD mice, while the non-phosphorylatable S72A mutant offers no protective effects.

Research Significance and Prospects
This study first reveals the neuroprotective role of the SIK2-GABARAPL2 signaling axis in AD models through autophagosome-lysosome fusion regulation, providing a novel molecular mechanism for autophagy dysfunction in AD. Future studies should further explore the regulatory mechanisms of this signaling axis and develop drugs targeting SIK2 or GABARAPL2 phosphorylation to enhance autophagy and improve AD pathology. Moreover, it is worth investigating whether this mechanism has broader implications in 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, reducing Aβ deposition and improving cognitive and synaptic function in AD model mice. It not only establishes the SIK2-GABARAPL2 axis as a new target for autophagy regulation but also provides potential therapeutic strategies for AD. The neuroprotective effects of the phospho-mimetic S72E mutant suggest that enhancing GABARAPL2 phosphorylation may represent a novel intervention approach for treating autophagy-deficient neurodegenerative diseases. Future studies should further explore the role of this signaling axis in various neurodegenerative disorders 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.