Microglial autophagy and other LC3-dependent pathways in neurodegeneration

Abstract

Autophagy is a conserved cellular clearance pathway that supports homeostasis by removing damaged or superfluous intracellular components. Within microglia, autophagy is emerging as a regulator of key processes that modify neurodegeneration, including phagocytosis, cytokine secretion, and senescence. Many studies that have examined the effect of disrupted autophagy on microglial functions have used genetic knockouts of the machinery required to conjugate microtubule-associated light chain 3 (LC3) to the autophagic membrane. However, much of this molecular machinery is also required for a set of distinct but related pathways known as the conjugation of ATG8s to single membranes (CASM). CASM includes processes of particular importance in microglia, such as LC3-associated phagocytosis and LC3-associated endocytosis. It is thus not clear which of the effects of the disruption of LC3 conjugation in microglia are attributable to the loss of autophagy or the loss of CASM function. In this review, we describe the mechanisms of autophagy and CASM and highlight the effects of the loss of these pathways on key microglial processes relevant to brain ageing and neurodegenerative diseases. We discuss recent literature that has revealed the effects of ageing and neurodegeneration on microglial autophagy, and the effects of microglial autophagy and/or CASM disruption on key microglial functions such as phagocytosis, cytokine secretion, and senescence. Finally, we discuss the potential therapeutic implications of these findings for neurodegeneration and highlight key unanswered questions for future research.

Keywords

Autophagy / macroautophagy / microglia / ageing / neurodegeneration / LC3-associated phagocytosis / LC3-associated endocytosis / conjugation of ATG8s to single membranes

Acknowledgements

We thank our colleagues in this research field and regret that, due to space constraints, we were unable to include all relevant literature on this topic.

Authors contribution

Palmer JE, Rubinsztein DC: Writing-original draft, writing review & editing.

Conflicts of interest

David C. Rubinsztein is an Editorial Board Member of Geromedicine. The author has consulted for or is a consultant for Drishti Discoveries, PAQ Therapeutics, MindRank AI, Retro Biosciences, Alexion Pharma International Operations Limited, Carlyle Investment Management LLC, Aladdin Healthcare Technologies Ltd, Nido Biosciences, ProtosBio, and is a co-founder of Acuity Technologies Ltd. The other author declares no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the UK Dementia Research Institute through UK DRI Ltd, principally funded by the Medical Research Council (to David C. Rubinsztein), the National Institute for Health Research Cambridge Biomedical Research Centre at Addenbrooke’s Hospital (to David C. Rubinsztein), and the Cambridge Trust, the Rutherford Foundation, and the Royal Society Te Apārangi of New Zealand (to Jennifer E. Palmer) (The programs do not have grant numbers).

Copyright

© The Author(s) 2026.

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