Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

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.

A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease

“…However, the experiments of Zhou et al on C. elegans and mice lacking sgk-1 (serum/ glucocorticoid regulated kinase-1) illustrated that a high level of mPTP opening induced by elevated autophagy unexpectedly shortens their lifespan [138], implying side effects maybe occur while enhancing autophagy. Numerous autophagy-modulating agents developed to treat AD, including the mechanistic target of rapamycin (mTOR)-dependent and mTOR-independent autophagyincluding agents (see Table 2) [165]. The master metabolic regulator mTOR can formulate two different functional complexes.…”

Natural Compounds and Autophagy: Allies Against Neurodegeneration

“…In recent years, the belief that autophagy is a druggable target and, consequently, its modulation a promising therapeutic opportunity for CNS diseases have been reported in several authoritative reviews (Morel et al, 2017;Scrivo et al, 2018;Condello et al, 2019;Djajadikerta et al, 2019;Mputhia et al, 2019;Peng et al, 2019;Thellung et al, 2019). However, the complex pathogenesis of neurodegeneration and a better knowledge of autophagy steps and upstream signaling pathways are necessary to extend promising results obtained in animal models to patients.…”

Biological Activities of Cyclic and Acyclic B-Type Laxaphycins in SH-SY5Y Human Neuroblastoma Cells

“…This process plays an important role in many pathologies such as cancer, diabetes and neurodegenerative diseases [ 16 ]. Therefore, much effort has been made in the search for new compounds capable of targeting the autophagic flux [ 17 , 18 ].…”