Trehalose as a promising therapeutic candidate for the treatment of Parkinson's disease

Khalifeh, Masoomeh; Barreto, George E.; Sahebkar, Amirhossein

doi:10.1111/bph.14623

Cited by 85 publications

(55 citation statements)

References 151 publications

(239 reference statements)

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“…Tre is an inducer of autophagy-lysosomal biogenesis by an unclear mechanism. It has demonstrated anti-inflammatory effects in many diseases [34][35][36]. In this study, Tre induced TFEB nuclear localization and upregulated TFEB expression in the lungs (Figure 4A-C) and AMs ( Figure 4D-E) of CS-treated mice.…”

Section: Tre Activates Tfeb and Affects Autophagy-associated Proteinssupporting

confidence: 52%

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

Shi

et al. 2020

Cells

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Silicosis is an occupational lung disease characterized by persistent inflammation and irreversible fibrosis. Crystalline silica (CS) particles are mainly phagocytized by alveolar macrophages (AMs), which trigger apoptosis, inflammation, and pulmonary fibrosis. Previously, we found that autophagy-lysosomal system dysfunction in AMs was involved in CS-induced inflammation and fibrosis. Induction of autophagy and lysosomal biogenesis by transcription factor EB (TFEB) nuclear translocation can rescue fibrotic diseases. However, the role of TFEB in silicosis is unknown. In this study, we found that CS induced TFEB nuclear localization and increased TFEB expression in macrophages both in vivo and in vitro. However, TFEB overexpression or treatment with the TFEB activator trehalose (Tre) alleviated lysosomal dysfunction and enhanced autophagic flux. It also reduced apoptosis, inflammatory cytokine levels, and fibrosis. Both pharmacologically inhibition of autophagy and TFEB knockdown in macrophages significantly abolished the antiapoptotic and anti-inflammatory effects elicited by either TFEB overexpression or Tre treatment. In conclusion, these results uncover a protective role of TFEB-mediated autophagy in silicosis. Our study suggests that restoration of autophagy-lysosomal function by Tre-induced TFEB activation may be a novel strategy for the treatment of silicosis.

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Section: Tre Activates Tfeb and Affects Autophagy-associated Proteinssupporting

confidence: 52%

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

Shi

et al. 2020

Cells

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“…13,35 Moreover, Tre is a natural disaccharide that has been considered as a new candidate in the therapy of neurodegenerative diseases. 36 As expected, Tre has a protective effect on Mn-induced mitochondrial and neurocyte damage. Our data showed that Tre pre-treatment could effectively ameliorate the loss of ΔΨm, ATP depletion and cell apoptosis.…”

Section: F I G U R E 6 Effects Of Mn Andsupporting

confidence: 59%

“…Tre has multiple biological functions, including anti‐inflammation, induction of autophagy, alleviation of oxidative stress and mitigation of ER stress . Moreover, Tre is a natural disaccharide that has been considered as a new candidate in the therapy of neurodegenerative diseases . As expected, Tre has a protective effect on Mn‐induced mitochondrial and neurocyte damage.…”

Section: Discussionmentioning

confidence: 81%

Effect of trehalose on manganese‐induced mitochondrial dysfunction and neuronal cell damage in mice

Liu

Jing

Liu

et al. 2019

Basic Clin Pharma Tox

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Chronic overexposure to manganese (Mn) has been verified to induce mitochondrial dysfunction, which is related to oxidative damage. The autophagic‐lysosomal degradation pathway plays a vital role in the removal of impaired mitochondria through a specific quality control mechanism termed mitophagy. However, trehalose functions as an inducer of autophagy by an mTOR‐independent mechanism, and little data report its effect on Mn‐induced mitochondrial dysfunction. To explore the possibility that trehalose could be effective in interfering with the Mn‐induced mitochondrial dysfunction, we used trehalose (2% and 4% (g/vol (mL))) in a mouse model of manganism. Our data showed that mice developed weary motor and behavioural deficits after exposure to Mn for 6 weeks. Overexposure to Mn resulted in mitochondrial dysfunction and neuronal cell damage in the basal nuclei of mice, which could be ameliorated by trehalose pre‐treatment. Moreover, our results indicated that trehalose pre‐treatment significantly reduced the oxidative damage and enhanced the activation of mitophagy. The findings clearly demonstrated that trehalose could relieve Mn‐induced mitochondrial and neuronal cell damage through its antioxidative and mitophagy‐inducing effects.

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“…It is noteworthy that despite the presence of trehalase in the gut, orally administered trehalose has been proven to exert significant biological effects in mouse models of many different diseases, such as Parkinson's, Alzheimer's, muscular dystrophy, Huntington's disease, ALS, prion's disease, OPMD, obesity, hepatic steatosis, diabetes, or chronic ischemia [35,53,54]. Thus, we cannot exclude that trehalose effects might occur, or at least count with contribution of indirect effects in peripheral energy metabolism and inflammatory pathways [55,56].…”

Section: Discussionmentioning

confidence: 99%

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

et al. 2020

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Background: Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is the most common of the dominantly inherited ataxias worldwide and is characterized by mutant ataxin-3 aggregation and neuronal degeneration. There is no treatment available to block or delay disease progression. In this work we investigated whether trehalose, a natural occurring disaccharide widely used in food and cosmetic industry, would rescue biochemical, behavioral and neuropathological features of an in vitro and of a severe MJD transgenic mouse model. Methods: Two MJD animal models, a lentiviral based and a transgenic model, were orally treated with 2% trehalose solution for a period of 4 and 30 weeks, respectively. Motor behavior (rotarod, grip strength and footprint patterns) was evaluated at different time points and neuropathological features were evaluated upon in-life phase termination. Results: Trehalose-treated MJD mice equilibrated for a longer time in the rotarod apparatus and exhibited an improvement of ataxic gait in footprint analysis. Trehalose-mediated improvements in motor behaviour were associated with a reduction of the MJD-associated neuropathology, as MJD transgenic mice treated with trehalose presented preservation of cerebellar layers thickness and a decrease in the size of ataxin-3 aggregates in Purkinje cells. In agreement, an improvement of neuropathological features was also observed in the full length lentiviral-based mouse model of MJD submitted to 2% trehalose treatment. Conclusions: The present study suggests trehalose as a safety pharmacological strategy to counteract MJD-associated behavioural and neuropathological impairments.

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Trehalose as a promising therapeutic candidate for the treatment of Parkinson's disease

Cited by 85 publications

References 151 publications

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

Trehalose Alleviates Crystalline Silica-Induced Pulmonary Fibrosis via Activation of the TFEB-Mediated Autophagy-Lysosomal System in Alveolar Macrophages

Effect of trehalose on manganese‐induced mitochondrial dysfunction and neuronal cell damage in mice

Trehalose alleviates the phenotype of Machado–Joseph disease mouse models

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