The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells

Casarejos, Marı́a José; Solano, Rosa M.; Gómez, Ana; Perucho, Juan; Yébenes, Justo Garcı́a de; Mena, María A.

doi:10.1016/j.neuint.2011.01.008

Cited by 102 publications

(77 citation statements)

References 51 publications

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“…Upon induction of autophagy, LC3 is converted from a cytosolic form (LC3-I) to a phosphatidylethanolamine-conjugated form (LC3-II) and thereby recruited to membranes of autophagosomes (31). Consistent with previous findings (21,22), trehalose induced a strong increase of LC3-II levels over time (Fig. 4A), resulting in elevated LC3-II/LC3-I ratios (Fig.…”

Section: Trehalose Impairs the Metabolism Of App And Decreases The Sesupporting

confidence: 90%

“…The present findings are surprising because trehalose has been shown to decrease cellular levels of the neurodegenerative disease-associated proteins huntingtin, ␣-synuclein, and phosphorylated tau in cellular and animal models (22)(23)(24), suggesting that trehalose promoted autophagy and lysosomal clearance of these proteins. A possible explanation for this contradiction might emerge from a recent study demonstrating the involvement of unconventional secretion of aggregated ␣-synuclein via exophagy in cases of impaired autophagosome-lysosome fusion or lysosomal function.…”

Section: Discussioncontrasting

confidence: 68%

“…In contrast to APP and its CTFs, tau, huntingtin, and ␣-synuclein are cytosolic proteins. It has been shown that inhibition of the proteasome by epoxomicin increased the levels of ␣-synuclein and phosphorylated tau and correlated with enhanced cell death (22). Thus, although autophagy is considered as the major pathway to degrade protein aggregates, a contribution of proteasomal degradation to the reduction of aggregate-prone proteins could not be excluded.…”

Section: Discussionmentioning

confidence: 99%

“…Trehalose is considered to enhance autophagic activity (21). It has been shown to promote the cellular clearance of pathogenic proteins like mutant huntingtin, ␣-synuclein (21,22), and phosphorylated tau (22)(23)(24) that are associated with Huntington, Parkinson, and Alzheimer diseases, respectively. However, the role of trehalose in the cellular metabolism of the Alzheimer disease-associated APP remains to be investigated.…”

mentioning

confidence: 99%

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Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, ␣-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-␤ peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.Alzheimer disease is characterized by the accumulation of extracellular amyloid plaques that contain aggregates of the amyloid ␤-peptide (A␤).5 A␤ is derived from the amyloid precursor protein by sequential proteolytic processing by ␤-and ␥-secretases (1, 2). The initial cleavage of amyloid precursor protein (APP) by ␤-secretase results in the secretion of the soluble ectodomain and the generation of a membrane-tethered C-terminal fragment (APP-CTF␤). Subsequently, APP-CTF␤ can be cleaved by ␥-secretase to liberate A␤ from cellular membranes (2). In an alternative pathway, APP can also be cleaved by ␣-secretase within the A␤ domain, thereby generating CTF␣. The subsequent cleavage of APP-CTF␣ by ␥-secretase results in secretion of a small peptide called p3 (2). It is important to note that APP is also metabolized by additional pathways, including proteasomal and lysosomal degradation (3-5).The metabolism of APP is also regulated by macroautophagy (herein referred to as autophagy), a lysosome-dependent degradative pathway for long lived proteins, organelles, and nutrient recycling (6, 7). Autophagy starts with the formation of double-membrane vesicles, the so-called autophagosomes, which further fuse with lysosomes to become autolysosomes for degradation of autophagosome contents by lysosomal hydrolases (8). Autophagy is an essential prosurvival pathway induced by a variety of stress factors, including nutrient deprivation, growth factor withdrawal, oxidative stress, infection, and hypoxia (9). These factors contribute to the etiology of multiple diseases such as cancer, stroke, heart disease, and infection (10). Eukaryotic cells have a basal autophagic activity under normal physiological conditions. Cells deficient in autophagy show diffuse abnormal protein accumulation and mitochondrial disorganization (11,12), suggesting that autophagy is important to maintain cellular homeostasis by eliminating protein aggregates and damaged organelles. Basal ...

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Section: Trehalose Impairs the Metabolism Of App And Decreases The Sesupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

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show abstract

“…Although multiple studies have demonstrated that trehalose confers beneficial effects on protein aggregation, behavior, and cell survival in an mTOR-independent manner [193], and leads to a dose-and time-dependent increase in the number of autophagosomes and autophagic markers [194], the specific autophagy-related molecular mechanisms have yet to be identified. A recent study in the mutant superoxide dismutase (SOD)1(G93A) mouse model of ALS suggests that trehalose treatment enhances autophagic flux.…”

Section: Trehalosementioning

confidence: 99%

Promoting Autophagic Clearance: Viable Therapeutic Targets in Alzheimer's Disease

Friedman

Qureshi

2015

Neurotherapeutics

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Many neurodegenerative disorders are characterized by the aberrant accumulation of aggregate-prone proteins. Alzheimer's disease (AD) is associated with the buildup of β-amyloid peptides and tau, which aggregate into extracellular plaques and neurofibrillary tangles, respectively. Multiple studies have linked dysfunctional intracellular degradation mechanisms with AD pathogenesis. One such pathway is the autophagy-lysosomal system, which involves the delivery of large protein aggregates/inclusions and organelles to lysosomes through the formation, trafficking, and degradation of double-membrane structures known as autophagosomes. Converging data suggest that promoting autophagic degradation, either by inducing autophagosome formation or enhancing lysosomal digestion, provides viable therapeutic strategies. In this review, we discuss compounds that can augment autophagic clearance and may ameliorate disease-related pathology in cell and mouse models of AD. Canonical autophagy induction is associated with multiple signaling cascades; on the one hand, the best characterized is mammalian target of rapamycin (mTOR). Accordingly, multiple mTOR-dependent and mTORindependent drugs that stimulate autophagy have been tested in preclinical models. On the other hand, there is a growing list of drugs that can enhance the later stages of autophagic flux by stabilizing microtubule-mediated trafficking, promoting lysosomal fusion, or bolstering lysosomal enzyme function. Although altering the different stages of autophagy provides many potential targets for AD therapeutic interventions, it is important to consider how autophagy drugs might also disturb the delicate balance between autophagosome formation and lysosomal degradation.

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Herbal Drugs

Malik¹

2017

Neuroprotective Effects of Phytochemicals in Neurological Disorders

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The accumulation of neurotoxic proteins, induced by proteasome inhibition, is reverted by trehalose, an enhancer of autophagy, in human neuroblastoma cells

Cited by 102 publications

References 51 publications

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Promoting Autophagic Clearance: Viable Therapeutic Targets in Alzheimer's Disease

Herbal Drugs

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