The central event driving neuronal activity is represented by synaptic transmission, a process that relies on regulated cycles of synaptic vesicle (SV) exocytosis and endocytosis at presynaptic terminal level. Neurons, polarized and perennial cells, to guarantee an efficient neurotransmitter release, to maintain cellular homeostasis and promote neuronal survival, are particularly dependent on efficient quality control pathways to continuously remove dysfunctional presynaptic proteins and organelles. The main mechanisms used by neurons to achieve these goals are endosomal sorting and autophagy, a highly conserved endo-lysosomal degradation pathway required to recycle basic nutrients by the clearance of damaged or aged proteins and organelles. Several presynaptic endocytic proteins have been shown to regulate both SV recycling and autophagy and defects in both pathways have been linked to neurodevelopmental abnormalities and neurodegeneration in mouse and humans. In 2017 we characterized the previously unknown protein APache (KIAA1107) as a neuronal-specific protein, novel interactor of the adaptor protein AP-2 essential in the regulation of neuronal development and SV cycle in vitro and in vivo. In this work, we intended to define APache functional role in neuronal autophagy by combining electron microscopy, immunofluorescence, live-cell imaging microscopy and biochemistry. We observed that APache is actually involved in autophagy: the induction of the process increases APache levels in mature neurons and, conversely, APache silencing leads to a severe accumulation of late-stage autophagosomes in neurons, also at synaptic level, due to autophagic blockade. Interestingly, APache expression is significantly reduced in the brain of sporadic Alzheimer’s disease patients. These data point to APache as a novel key regulator of neuronal autophagy. Its altered levels, resulting in defective autophagy, may contribute to the precocious cellular alterations and synaptic dysfunctions observed in neurodegenerative diseases. The further elucidation of its functional role in neurons and of its precise molecular mechanism will help our understanding of the physiology and pathology of synaptic function.

Role of the novel neuronal protein APache in autophagy

PARISI, BARBARA
2022-07-08

Abstract

The central event driving neuronal activity is represented by synaptic transmission, a process that relies on regulated cycles of synaptic vesicle (SV) exocytosis and endocytosis at presynaptic terminal level. Neurons, polarized and perennial cells, to guarantee an efficient neurotransmitter release, to maintain cellular homeostasis and promote neuronal survival, are particularly dependent on efficient quality control pathways to continuously remove dysfunctional presynaptic proteins and organelles. The main mechanisms used by neurons to achieve these goals are endosomal sorting and autophagy, a highly conserved endo-lysosomal degradation pathway required to recycle basic nutrients by the clearance of damaged or aged proteins and organelles. Several presynaptic endocytic proteins have been shown to regulate both SV recycling and autophagy and defects in both pathways have been linked to neurodevelopmental abnormalities and neurodegeneration in mouse and humans. In 2017 we characterized the previously unknown protein APache (KIAA1107) as a neuronal-specific protein, novel interactor of the adaptor protein AP-2 essential in the regulation of neuronal development and SV cycle in vitro and in vivo. In this work, we intended to define APache functional role in neuronal autophagy by combining electron microscopy, immunofluorescence, live-cell imaging microscopy and biochemistry. We observed that APache is actually involved in autophagy: the induction of the process increases APache levels in mature neurons and, conversely, APache silencing leads to a severe accumulation of late-stage autophagosomes in neurons, also at synaptic level, due to autophagic blockade. Interestingly, APache expression is significantly reduced in the brain of sporadic Alzheimer’s disease patients. These data point to APache as a novel key regulator of neuronal autophagy. Its altered levels, resulting in defective autophagy, may contribute to the precocious cellular alterations and synaptic dysfunctions observed in neurodegenerative diseases. The further elucidation of its functional role in neurons and of its precise molecular mechanism will help our understanding of the physiology and pathology of synaptic function.
accumulation; Alzheimer; APache; AP-2; autophagy; autophagosome; autophagic block; autophagic blockade; CME; dynein; endocytosis; KIAA; KIAA1107; neuron; neuronal autophagy; neurodegeneration; synapse; synaptic vesicle; transport
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/1090471
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