AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma

Molecular Neurodegeneration

Florence Dotigny¹  Jorge L. Cueva Vargas²  Jessica Agostinone²  Nicolas Belforte²  Luis Alarcon-Martinez²  Deborah Villafranca-Baughman²  Adriana Di Polo² 

[1]Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), 900 Saint Denis Street, H2X 0A9, Montréal, Québec, Canada

[2]Department of Neuroscience, Université de Montréal, Succursale centre-ville 6128, H3C 3J7, Montréal, Québec, Canada

[3]Centre de recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), 900 Saint Denis Street, H2X 0A9, Montréal, Québec, Canada

关键词: Adenosine monophosphate-activated protein kinase;    Metabolic stress;    Mammalian target of rapamycin;    Glaucoma;    Neurodegeneration;   

DOI  :  10.1186/s13024-021-00466-z

来源: Springer

【 摘 要 】

BackgroundThe maintenance of complex dendritic arbors and synaptic transmission are processes that require a substantial amount of energy. Bioenergetic decline is a prominent feature of chronic neurodegenerative diseases, yet the signaling mechanisms that link energy stress with neuronal dysfunction are poorly understood. Recent work has implicated energy deficits in glaucoma, and retinal ganglion cell (RGC) dendritic pathology and synapse disassembly are key features of ocular hypertension damage.ResultsWe show that adenosine monophosphate-activated protein kinase (AMPK), a conserved energy biosensor, is strongly activated in RGC from mice with ocular hypertension and patients with primary open angle glaucoma. Our data demonstrate that AMPK triggers RGC dendrite retraction and synapse elimination. We show that the harmful effect of AMPK is exerted through inhibition of the mammalian target of rapamycin complex 1 (mTORC1). Attenuation of AMPK activity restores mTORC1 function and rescues dendrites and synaptic contacts. Strikingly, AMPK depletion promotes recovery of light-evoked retinal responses, improves axonal transport, and extends RGC survival.ConclusionsThis study identifies AMPK as a critical nexus between bioenergetic decline and RGC dysfunction during pressure-induced stress, and highlights the importance of targeting energy homeostasis in glaucoma and other neurodegenerative diseases.

【 授权许可】

CC BY