Abstract
The aim of this review is to critically analyze promises and limitations of pharmacological inducers of autophagy against protein misfolding-associated neurodegeneration. Effective therapies against neurodegenerative disorders can be developed by regulating the “self-defense” equipment of neurons, such as autophagy. Through the degradation and recycling of the intracellular content, autophagy promotes neuron survival in conditions of trophic factor deprivation, oxidative stress, mitochondrial and lysosomal damage, or accumulation of misfolded proteins. Autophagy involves the activation of self-digestive pathways, which is different for dynamics (macro, micro and chaperone-mediated autophagy), or degraded material (mitophagy, lysophagy, aggrephagy). All neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which causes the inability to remove the neurotoxic oligomers of misfolded proteins. Pharmacological activation of autophagy is typically achieved by blocking the kinase activity of mammalian target of rapamycin (mTOR) enzymatic complex 1 (mTORC1), removing its autophagy suppressor activity observed under physiological conditions; acting in this way, rapamycin provided the first proof of principle that pharmacological autophagy enhancement can induce neuroprotection through the facilitation of oligomers’ clearance. The demand for effective disease-modifying strategies against neurodegenerative disorders is currently stimulating the development of a wide number of novel molecules, as well as the re-evaluation of old drugs for their pro-autophagic potential.
Highlights
Neurons, as all long-lived cells, must face a ceaseless flow of damage, including reduction of trophic factor production and/or activity, oxidative damage of cytoplasmic structures, and accumulation of lipofuscins and misfolded proteins
In the context of drug repositioning [57,58], a growing number of old and novel drugs, so far placed in human therapy to treat a wide number of pathologies, often unrelated to neurodegeneration, are currently under re-evaluation as autophagy inducers to be introduced as disease-modifying strategies against Protein Conformational Disorders (PCDs) of central nervous system (CNS)
In addition to suppressing mTOR complex 1 (mTORC1) kinase activity, induces the dephosphorylation of AMBRA 1, which precedes the activation of ULK and phagophore-forming enzymatic complex UKC and the class III phosphatidylinositol 3-phosphate kinase, both representing the initial steps of autophagy [100,101]
Summary
As all long-lived cells, must face a ceaseless flow of damage, including reduction of trophic factor production and/or activity, oxidative damage of cytoplasmic structures, and accumulation of lipofuscins and misfolded proteins. A recent theory claims that all these neurodegenerative diseases recognize the conformational misfolding of specific proteins, whose function in the brain is often obscure, as a common mechanism of neurotoxicity [12] Among these disorders, the differences in the mechanisms by which protein misfolding occurs may account for the heterogeneous etiology of the diseases; neuronal loss is likely caused by the generation of soluble protein oligomers along the process of aggregation and amyloidogenesis that follows the misfolding [13]. The differences in the mechanisms by which protein misfolding occurs may account for the heterogeneous etiology of the diseases; neuronal loss is likely caused by the generation of soluble protein oligomers along the process of aggregation and amyloidogenesis that follows the misfolding [13] Another important pathogenic event that unifies PCDs and, to a certain extent, occurs during aging, is represented by autophagy alterations and impaired proteostasis [14]. A promising outcome of such unifying pathogenic hypothesis regards the possibility to set up a common neuroprotective strategy against several different forms of CNS amyloidosis through the pharmacological enhancement or restoration of the autophagic flow [16]
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