Interdependency Between Autophagy and Synaptic Vesicle Trafficking: Implications for Dopamine Release

Abstract

Autophagy (ATG) and the Ubiquitin Proteasome (UP) are the main clearing systems of eukaryotic cells, in that being ultimately involved in degrading damaged and potentially harmful cytoplasmic substrates. Emerging evidence implicates that, in addition to their classic catalytic function in the cytosol, autophagy and the proteasome act as modulators of neurotransmission, inasmuch as they orchestrate degradation and turnover of synaptic vesicles (SVs) and related proteins. These findings are now defining a novel synaptic scenario, where clearing systems and secretory pathways may be considered as a single system, which senses alterations in quality and distribution (in time, amount and place) of both synaptic proteins and neurotransmitters. In line with this, in the present manuscript we focus on evidence showing that, a dysregulation of secretory and trafficking pathways is quite constant in the presence of an impairment of autophagy-lysosomal machinery, which eventually precipitates synaptic dysfunction. Such a dual effect appears not to be just incidental but it rather represents the natural evolution of archaic cell compartments. While discussing these issues, we pose a special emphasis on the role of autophagy upon dopamine (DA) neurotransmission, which is early affected in several neurological and psychiatric disorders. In detail, we discuss how autophagy is engaged not only in removing potentially dangerous proteins, which can interfere with the mechanisms of DA release, but also the fate of synaptic DA vesicles thus surveilling DA neurotransmission. These concepts contribute to shed light on early mechanisms underlying intersection of autophagy with DA-related synaptic disorders.

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update

“…Once thought to play a merely housekeeping role by removing misfolded proteins or compromised organelles, neuronal autophagy is now regarded as a finely tuned surveillance system, which operates in neurons to guarantee synaptic integrity and function. This occurs, for instance, through degradation and turnover of both pre-and post-synaptic substrates, including synaptic vesicles, scaffold proteins, and neurotransmitter receptors [23][24][25]. In keeping with this, failure of mTOR-dependent autophagy was recently shown to promote aberrant synaptic clustering of GABA A receptors and subsequent imbalance of excitation-inhibition in the brain, which might be key for epileptogenesis [26].…”

“…Importantly, autophagy is implicated in neurotransmitter release as well as the internalization and endolysosomal turnover of neurotransmitter receptors beyond GABAergic ones ( Figure 1). For instance, autophagy induction following inhibition of either GSK3β or mTOR regulates dopamine and glutamate release as well as the internalization of glutamate receptors [24,[52][53][54][55]. The latter is associated with a decrease in the amount of intracellular Ca 2+ and reduced excitotoxicity [55][56][57][58], which are key events implicated in seizure-induced neuronal damage ( Figure 1).…”

“…This would not be surprising since autophagy regulates a variety of cell functions that are implicated in neurodevelopmental and neurological disorders, including epilepsy. In fact, besides coping with harmful events such as oxidative damage and mitochondrial alterations, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, axon guidance, dendritic spine architecture and pruning, vesicular release, and synaptic plasticity [23][24][25]. Once thought to play a merely housekeeping role by removing misfolded proteins or compromised organelles, neuronal autophagy is now regarded as a finely tuned surveillance system, which operates in neurons to guarantee synaptic integrity and function.…”

Endosomal trafficking leads the way in Parkinson's disease

“…However, compromised lysosomal‐autophagic processing may contribute to the inclusion pathology observed in many neurodegenerative disorders, not only the selective vulnerability of midbrain dopaminergic neurons. It is also important to recognize that EMTP genes may encode proteins involved in more than one aspect of endosomal biology and in specialized cell types . Mutations in LRRK2 , SNCA, VPS35 and DNAJC13 , linked to late‐onset parkinsonism that most closely resembles idiopathic PD, may subtly impair synaptic/early endosomal processes as well as endosomal autophagy .…”

“…It is also important to recognize that EMTP genes may encode proteins involved in more than one aspect of endosomal biology and in specialized cell types. 17 Mutations in LRRK2, SNCA, VPS35 and DNAJC13, linked to late-onset parkinsonism that most closely resembles idiopathic PD, may subtly impair synaptic/early endosomal processes 7,18-20 as well as endosomal autophagy. [21][22][23][24] Although molecular mechanisms of dopaminergic axonal arbor degeneration may be separate and distinct from those of neuronal soma, 25 many of these protein components appear to be important in both.…”