Pharmacological enhancement of TFEB-mediated autophagy alleviated neuronal death in oxidative stress-induced Parkinson’s disease models

Abstract

Autophagy, a conserved cellular degradation and recycling process, can be enhanced by nutrient depletion, oxidative stress or other harmful conditions to maintain cell survival. 6-Hydroxydopamine/ascorbic acid (6-OHDA/AA) is commonly used to induce experimental Parkinson's disease (PD) lesions by causing oxidative damage to dopaminergic neurons. Activation of autophagy has been observed in the 6-OHDA-induced PD models. However, the mechanism and exact role of autophagy activation in 6-OHDA PD model remain inconclusive. In this study, we report that autophagy was triggered via mucolipin 1/calcium/calcineurin/TFEB (transcription factor EB) pathway upon oxidative stress induced by 6-OHDA/AA. Interestingly, overexpression of TFEB alleviated 6-OHDA/AA toxicity. Moreover, autophagy enhancers, Torin1 (an mTOR-dependent TFEB/autophagy enhancer) and curcumin analog C1 (a TFEB-dependent and mTOR-independent autophagy enhancer), significantly rescued 6-OHDA/AA-induced cell death in SH-SY5Y cells, iPSC-derived DA neurons and mice nigral DA neurons. The behavioral abnormality of 6-OHDA/AAtreated mice can also be rescued by Torin 1 or C1 administration. The protective effects of Torin 1 and C1 can be blocked by autophagy inhibitors like chloroquine (CQ) or by knocking down autophagy-related genes TFEB and ATG5. Taken together, this study supports that TFEB-mediated autophagy is a survival mechanism during oxidative stress and pharmacological enhancement of this process is a neuroprotective strategy against oxidative stress-associated PD lesions.

The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects

“…A large body of evidence converges in demonstrating that curcumin supplementation confers neuroprotection by rescuing ATG. For instance, curcumin counteracts 6-OHDA-induced cell death in SH-SY5Y cells by enhancing the ATG-dependent clearance of damaged mitochondria and removal of excess ROS [ 26 ]. Curcumin also counteracts mitochondrial damage by enhancing mitochondria ATG (i.e., mitophagy), which selectively removes damaged and/or aged mitochondria [ 27 ].…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…The stilbene group is best exemplified by resveratrol, a well-known phenolic compound found in red wine, grape, and virgin olive oil, which has shown remarkable neuroprotective and anti-aging properties in a plethora of experimental models [ 50 , 58 , 59 , 65 , 69 , 97 , 98 , 99 , 100 , 101 , 102 ]. Finally, phenolic acids, which can be subdivided into hydroxybenzoic acids (such as syringic and gallic acids) [ 103 , 104 , 105 ] and hydroxycinnamic acids (such as ferulic, caffeic, and chlorogenic acids, including the derivatives rosmarinic acid, salvianolic acid, and curcumin), have shown encouraging results in various experimental models of neurodegeneration, neurotoxicity and neurological insults [ 3 , 54 , 57 , 62 , 66 , 70 , 106 , 107 ].…”

“…In the last decades, the search for an effective and potentially safe strategy to combat oxidative stress-mediated neuronal damage has increasingly prompted the investigation of naturally occurring compounds as antioxidant agents. The attenuation of oxidative stress by bioactive compounds belonging to different classes of phytochemicals including (i) flavonoids (quercetin, kaempferol and myricetin, scutellarin, baicalin, apigenin, catechins, epigallocatechin, and genistein) [ 52 , 61 , 81 , 82 , 83 , 88 , 94 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 ]; (ii) phenolic acids (syringic, gallic, caffeic, chlorogenic and salvianolic acids, and curcumin) [ 70 , 103 , 104 , 105 , 138 , 139 , 140 , 141 , 142 , 143 ]; (iii) flavonolignans (silymarin) [ 96 ]; (iv) stilbenes (resveratrol) [ 59 , 65 , 97 , 98 , 144 ]; (v) terpenes (bacosides/bacopasides, withanolides, and the carotenoids lutein and zeaxanthin) [ 7 , 110 , 113 , 115 , 145 , 146 , 147 ]; (vi) alkaloids (berberine and caffeine) [ 148 , 149 ]; (vii) glucosinolates (sulforaphane) and polyamines (spermine/spermidine) [ 123 , 124 ,…”

“…As shown in various experimental models of neurodegeneration, a failure in the autophagy machinery may predispose to neuronal injury due to extreme oxidative damage intermingling with protein overload and neuroinflammation, while rescuing autophagy may confer protection to grant cell survival [ 7 , 10 , 21 , 24 , 28 , 29 ]. It is remarkable that a wide variety of phytochemicals, including phenolic compounds such as anthocyanins, stilbenes (resveratrol), monophenols (caffeic acid, gallic acid), glucosides and flavonoids (catechin, epicatechin, quercetin, myricetin), and also nitrogen-containing compounds (berberine and spermine), are capable of stimulating autophagy to confer neuroprotection through either Akt/mTOR inhibition or AMPK/SIRT1 or TFEB activation [ 3 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. Thus, in the next section, we discuss evidence bridging the antioxidant effects of these compounds with autophagy-related neuroprotection.…”

“…In this frame, it is remarkable that the common neuroprotective, antioxidant, and anti-inflammatory effects produced by several phytochemicals are associated with rescuing autophagy, meanwhile counteracting behavioral alterations, mitochondrial damage as well as intracellular accumulation and release of potentially detrimental substrates [ 3 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. As recently reviewed, the neuroprotective effects of phytochemicals involve also a double-faceted, yet controversial modulation of the proteasome pathway, which will not be discussed in detail herewith [ 9 ].…”