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

• Published in: Molecular neurodegeneration Vol. 16; no. 1; p. 43
• Main Authors: Belforte, Nicolas, Agostinone, Jessica, Alarcon-Martinez, Luis, Villafranca-Baughman, Deborah, Dotigny, Florence, Cueva Vargas, Jorge L, Di Polo, Adriana
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29-06-2021; BioMed Central; BMC
• Subjects: Adenosine kinase; Adenosine monophosphate-activated protein kinase; Adenylate Kinase - metabolism; Adenylic acid; AMP; Animals; Antibodies; Axonal transport; Biosensors; Canada; Cornea; Dendrites; Dendrites - pathology; Disease transmission; Energy; Energy balance; Energy conservation; Enzyme Activation - physiology; Gene expression; Glaucoma; Glaucoma, Open-Angle - metabolism; Glaucoma, Open-Angle - pathology; Homeostasis; Humans; Hypertension; Kinases; Light effects; Mammalian target of rapamycin; Massachusetts; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolic stress; Metabolism; Mice; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurophysiology; Optic nerve; Protein kinase; Protein kinases; Proteins; Rapamycin; Retina; Retinal ganglion cells; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Synapse elimination; Synapses - pathology; Synaptic transmission; TOR protein; Canada; Massachusetts; Glaucoma; Adenosine monophosphate-activated protein kinase; Neurodegeneration; Metabolic stress; Mammalian target of rapamycin
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-021-00466-z

The 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.
We 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.
This 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.