Protective effects of trehalose against Mn‐induced α‐synuclein oligomerization in mice: Involvement of oxidative stress and autophagy

Abstract

Overexposure to manganese (Mn) is widely known to induce alpha-synuclein (α-Syn) oligomerization, which has been attributed to the oxidative damage of α-Syn protein.Trehalose has been shown to induce autophagy and serve as a chemical chaperone, but little information has been reported about its effect on Mn-induced α-Syn oligomerization. In this study, we investigate whether trehalose can effectively interfere with Mn-induced α-Syn oligomerization, using different concentrations of trehalose (2% and 4% (g/vol [mL])) in a mouse model of manganism. After 6 weeks of exposure to Mn, both oxidative stress and autophagy were activated and resulted in α-Syn oligomerization and neuronal cell damage in the mouse brain tissue. Our results also revealed that pretreatment with trehalose significantly reduced the oxidative damage to α-Syn protein and increased autophagy activation. These findings clearly demonstrated that trehalose can relieve Mn-induced α-Syn oligomerization and neuronal cell damage through its anti-oxidative and autophagy-inducing effects. K E Y W O R D Salpha-synuclein oligomerization, autophagy, manganese, oxidive stress, trehalose

Alimentary Treatment with Trehalose in a Pharmacological Model of Alzheimer’s Disease in Mice: Effects of Different Dosages and Treatment Regimens

“…The result obtained appears to differ from some previous findings. In particular, treatment with 2% and 4% trehalose solution similarly enhanced autophagy in the brain tissue in a mouse model of Mn-induced α-synuclein oligomerization [ 23 ]. In rats, treatment with 2% and 5% trehalose solution had similar effects on autophagy induction in the brain, while 0.5% solution was ineffective in a AAV1/2-based rat model of Parkinson’s disease [ 18 ].…”

“…The safety of taking high doses of trehalose [ 15 , 16 ], the efficiency of the oral and parenteral administration of the drug [ 17 ], the dose dependence of the therapeutic effect of the drug [ 18 ], the effects of continuous treatment [ 13 , 17 ] or intermittent regimen [ 19 ], as well as the age-dependence, [ 13 ] have been researched. The studied concentrations of trehalose solution in the diet range from 1% to 5%, with different amplitudes of the achieved autophagic response [ 18 , 20 , 21 , 22 , 23 ]. A 2% concentration of trehalose in the drinking water is considered standard to induce neuroprotective effects in laboratory rodents [ 18 , 24 ].…”

Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies

“…Trehalose is a disaccharide comprised of two glucose molecules which is synthesized in bacteria, fungi, plants, and invertebrate animals. Trehalose has been shown to afford protective effects against Mn-induced neurotoxicity in the murine brain by increasing autophagy activation along with attenuation of Mn-induced oxidative stress and α-Syn oligomerization ( Jing et al, 2020 ). Trehalose mitigated Mn-induced PINK1/parkin-dependent mitophagy dysregulation by attenuating Mn-increased cleaved-poly (ADP-ribose) polymerase (PARP) and mitochondria-containing autophagic lysosomes, resulting in inhibition of Mn-induced mitochondrial damage and apoptosis in mice ( Liu et al, 2019 ).…”

“…Several compounds such as estrogens and riluzole attenuated Mn-induced glutamatergic excitotoxic neuronal injury by upregulating astrocytic glutamate transporters such as excitatory amino acid transporter 1 (EAAT1) and EAAT2 [glutamate-aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) in rodents, respectively] ( Fumagalli et al, 2008 ; Lee et al, 2009a ). A disaccharide trehalose attenuated Mn-induced neurotoxicity by modulating Mn-impaired autophagy and mitophagy ( Liu et al, 2019 ; Jing et al, 2020 ). Chelating agents such as ethylenediaminetetraacetic acid (EDTA) ( Discalzi et al, 2000 ) and para-aminosalicylic acid (PAS) have been shown to reduce acute Mn toxicity by promoting Mn excretion from the body ( Jiang et al, 2006 ; Zheng et al, 2009 ).…”