#NeuroConCiencia| Glial-specific regulation of endocytosis controls neuronal function and survival

• Speakers: Dra. Tania López-Hernández, Investigadora Ramón y Cajal · Universitat de Barcelona.

Language: english

Abstract

Endocytosis is essential for several critical cellular processes, such as nutrient uptake, plasma membrane remodeling, cell adhesion, intracellular signaling or neurotransmission. Neuron-specific roles of endocytosis have been extensively studied as neurotransmission crucially relies on efficient endocytosis for sustaining efficient communication between neurons by retrieving synaptic vesicle proteins after the secretion of neurotransmitters. Thus, defects in the endocytosis-dependent reformation of synaptic vesicles has dramatic consequences such as epilepsy and premature death. However, compared to neurons much less is known about the roles of endocytosis in glia cells. Astrocytes are the most numerous cells in the mammalian central nervous system where they fulfill numerous crucial functions for proper brain functioning ranging from neurotransmitter uptake, supply of nutrients, control of osmolarity and pH to modulation of excitability during synaptic transmission by the release of neuroactive substances (e.g. glutamate, ATP, D-serine). Thus, it is very well acknowledged that astrocyte impairment contribute to neuronal dysfunction in many neurological disorders like Alzheimer´s and Parkinson´s diseases among others. However, despite the wealth of information about the membrane proteins involved in astrocytic functions (e.g. neurotransmitter transporters), the relationship between these processes and endocytic pathways in glial cells under normal and pathological conditions remains unclear. We will discuss about the crucial role of endocytic adaptors as regulators of synaptic vesicle composition and function and how their malfunction might contribute to seizures in epilepsy syndromes, how glial-specific regulation of endocytosis controls neuronal function and survival highlighting non-cell autonomous mechanisms of neurodegeneration and how endocytic adaptors can control signaling networks like lysosomal biogenesis as part of an osmoprotective response which by transcriptional control of the autophagy/lysosome system through endocytic regulation of ion homeostasis, manages to adapt the cellular capacity to cope with the accumulation of damaged or aggregated proteins caused by deshidratation or hypertonic stress, being of potential relevance to human diseases such as neurodegeneration or intellectual disability.

Bullet point list:

• AP-2 is a dedicated endocytic adaptor that regulates the post-exocytosis sorting of selective synaptic vesicle proteins in an activity-dependent manner in response to a wide range of stimuli.
• Pathological relevance in humans: changes in synaptic vesicle protein composition compromise neurotransmission and give rise to epileptic seizures.
• Glial AP-2/clathrin-mediated endocytosis is crucial for fine tuning ion homeostasis and assisting proper glutamate uptake. · Hyperexcitability elicited by the AP-2 epileptogenic variant might result from defective astrocyte-mediated glutamate clearance due to impaired re-uptake into astrocytes.
• Inter-organellar communication via ion gradients: endocytosis controls cellular ion homeostasis to govern lysosomal gene expression as a cellular response to hypertonic stress.
• Alterations in cellular ion homeostasis may underlie X-linked intellectual disability caused by mutations in NHE7 in humans.

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