Dysfunctional Autophagy and Endolysosomal System in Neurodegenerative Diseases: Relevance and Therapeutic Options

Abstract

Autophagy and endolysosomal trafficking are crucial in neuronal development, function and survival. These processes ensure efficient removal of misfolded aggregation-prone proteins and damaged organelles, such as dysfunctional mitochondria, thus allowing the maintenance of proper cellular homeostasis. Beside this, emerging evidence has pointed to their involvement in the regulation of the synaptic proteome needed to guarantee an efficient neurotransmitter release and synaptic plasticity. Along this line, an intimate interplay between the molecular machinery regulating synaptic vesicle endocytosis and synaptic autophagy is emerging, suggesting that synaptic quality control mechanisms need to be tightly coupled to neurosecretion to secure release accuracy. Defects in autophagy and endolysosomal pathway have been associated with neuronal dysfunction and extensively reported in Alzheimer's, Parkinson's, Huntington's and amyotrophic lateral sclerosis among other neurodegenerative diseases, with common features and emerging genetic bases. In this review, we focus on the multiple roles of autophagy and endolysosomal system in neuronal homeostasis and highlight how their defects probably contribute to synaptic default and neurodegeneration in the above-mentioned diseases, discussing the most recent options explored for therapeutic interventions.

Keywords: autophagy; endocytosis; lysosomes; neurodegenerative diseases; synapse.

FIGURE 1

Schematic overview of autophagy and endolysosomal trafficking at the synapse. Local regulation of protein turnover occurs via autophagy (either non-selective and selective, e.g., mitophagy and aggrephagy) and the endolysosomal system (Rab5/Rab35/Rab7-dependent pathway), which can be stimulated by neuronal activity and nutrient depletion. In particular, metabolic signals activated upon nutrient restriction lead to mTORC1 inhibition and robust autophagy activation in many tissues. However, conflicting results have been raised as to whether starvation or mTORC1 inhibition are able to efficiently induce autophagy in neurons. mTORC1-independent pathways also exist (e.g., trehalose-induced) but are poorly characterized. At the presynaptic terminal, synaptic vesicle (SV) components retrieved after neurotransmitter release (e.g., by clathrin-mediated endocytosis) can transit through the endosomal compartment to be recycled back as newly formed SVs or be directed via late endosomes to lysosomes for degradation. Alternatively, SVs can be degraded via autophagy with a Rab26-dependent mechanism. Several presynaptic endocytic factors (e.g., Endophilin A, Synaptojanin1, AP-2) are implicated in the regulation of synaptic autophagy. Autophagosomes fuse with late endosomes to generate amphisomes and are transported along microtubules back to the soma, where fusion with lysosomes allows the digestion and recycling of cargoes. Autophagosomes can also act as signaling organelles, e.g., modulating neurotrophin-mediated TrkB signaling. Postsynaptically, autophagy and the endolysosomal system regulate neurotransmitter receptor trafficking and degradation.