Trehalose decreases mutant SOD1 expression and alleviates motor deficiency in early but not end-stage amyotrophic lateral sclerosis in a SOD1-G93A mouse model
“…Trehalose treatment increased the median life span of the naglu –/ – mice by 6.4 weeks ( P < 0.0001) (Figure 1(a)). Trehalose did not affect the body weight (Figure 1(b)) and did not cause any obvious adverse effects in WT mice, which is consistent with previous reports [34,37,41,42]. 10.1080/15548627.2018.1474313-F0001Figure 1.Trehalose treatment increases the life span and reduces hyperactivity and anxiety-related behavior in naglu −/- mice.…”
Section: Resultssupporting
confidence: 90%
“…Together with our data from this study, these findings indicate that trehalose administration can be regarded as a viable potential strategy for neurodegenerative diseases that are characterized by accumulation of intracellular material due to impairment of enzyme-based catabolic pathways such as lysosomal degradation of glycosaminoglycans. Consistent with previous studies investigating the long-term effects of trehalose [34], our data demonstrate that trehalose treatment is more effective at an early stage of disease progression. While the effects of trehalose on neuronal function have not been measured previously, our electrophysiological studies show that reduction of inflammation and protection of photoreceptors are accompanied by improved neuronal function.…”
The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus
“…Trehalose treatment increased the median life span of the naglu –/ – mice by 6.4 weeks ( P < 0.0001) (Figure 1(a)). Trehalose did not affect the body weight (Figure 1(b)) and did not cause any obvious adverse effects in WT mice, which is consistent with previous reports [34,37,41,42]. 10.1080/15548627.2018.1474313-F0001Figure 1.Trehalose treatment increases the life span and reduces hyperactivity and anxiety-related behavior in naglu −/- mice.…”
Section: Resultssupporting
confidence: 90%
“…Together with our data from this study, these findings indicate that trehalose administration can be regarded as a viable potential strategy for neurodegenerative diseases that are characterized by accumulation of intracellular material due to impairment of enzyme-based catabolic pathways such as lysosomal degradation of glycosaminoglycans. Consistent with previous studies investigating the long-term effects of trehalose [34], our data demonstrate that trehalose treatment is more effective at an early stage of disease progression. While the effects of trehalose on neuronal function have not been measured previously, our electrophysiological studies show that reduction of inflammation and protection of photoreceptors are accompanied by improved neuronal function.…”
The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs.Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus
“…We also wanted to induce autophagy in a way that would have the lowest probability of toxic effects. For that reason, we decided to use trehalose, a nontoxic disaccharide that has been shown to induce autophagy and to have neuroprotective effects in animal models of Huntington disease, Alzheimer's disease, Parkinson's disease, ALS, and maternal diabetes-associated neural tube defects in the embryo (13,(15)(16)(17)(18)(19)(20). In addition to the positive effects of trehalose in neurodegenerative diseases, there is also evidence that trehalose may have a beneficial effect on impaired endothelial cells in ageing arteries, a risk factor for cardiovascular disease (49).…”
Section: Discussionmentioning
confidence: 99%
“…Trehalose can inhibit polyglutamine aggregation in vitro (13), and the protective function of trehalose is also manifest when trehalose is introduced exogenously into mammalian cells. Treatment of cells with trehalose can induce the clearance of mutant huntingtin and alpha-synuclein (14) and is able to decrease the level of toxic aggregates and reduce morbidity and mortality in animal models of Huntington disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) (13,(15)(16)(17)(18). It is known that neural tube defects are greatly increased in the offspring of women with pregestational diabetes.…”
Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. Previous studies have shown that the induction of autophagy can inhibit the replication of several different types of DNA and RNA viruses. The goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of HCMV. Most prior studies have used agents that induce autophagy via inhibition of the mTOR pathway. However, since HCMV infection alters the sensitivity of mTOR kinase-containing complexes to inhibitors, we sought an alternative method of inducing autophagy. We chose to use trehalose, a nontoxic naturally occurring disaccharide that is found in plants, insects, microorganisms, and invertebrates but not in mammals and that induces autophagy by an mTOR-independent mechanism. Given the many different cell targets of HCMV, we proceeded to determine whether trehalose would inhibit HCMV infection in human fibroblasts, aortic artery endothelial cells, and neural cells derived from human embryonic stem cells. We found that in all of these cell types, trehalose induces autophagy and inhibits HCMV gene expression and production of cell-free virus. Treatment of HCMV-infected neural cells with trehalose also inhibited production of cell-associated virus and partially blocked the reduction in neurite growth and cytomegaly. These results suggest that activation of autophagy by the natural sugar trehalose or other safe mTOR-independent agents might provide a novel therapeutic approach for treating HCMV disease.
IMPORTANCEHCMV infects multiple cell types in vivo, establishes lifelong persistence in the host, and can cause serious health problems for fetuses and immunocompromised individuals. HCMV, like all other persistent pathogens, has to finely tune its interplay with the host cellular machinery to replicate efficiently and evade detection by the immune system. In this study, we investigated whether modulation of autophagy, a host pathway necessary for the recycling of nutrients and removal of protein aggregates, misfolded proteins, and pathogens, could be used to target HCMV. We found that autophagy could be significantly increased by treatment with the nontoxic, natural disaccharide trehalose. Importantly, trehalose had a profound inhibitory effect on viral gene expression and strongly impaired viral spread. These data constitute a proof-of-concept for the use of natural products targeting host pathways rather than the virus itself, thus reducing the risk of the development of resistance to treatment. H uman cytomegalovirus (HCMV) infects multiple cell types, including endothelial, smooth muscle, epithelial, and fibroblast cells, monocytes/macrophages, bone marrow progenitor cells, and cells of the neural lineage, and establishes lifelong persistence in the host (for a review, see reference 1). Seroprevalence is high in the general population, and in most healthy individuals, the in...
“…Administration of trehalose also facilitated induction of autophagy and autophagy-mediated degradation of mutant SOD1, thereby alleviating the severity of disease [107][108][109]. Besides of stimulating AMPK, trehalose can induce heat shock protein B8 (HspB8), which also facilitates autophagy with clearing autophagic substrates including mutant SOD1 [110,111].…”
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons associated with the abnormal aggregation of ubiquitinated proteins. The molecular mechanisms underlying the pathogenesis of ALS remain unclear, however. Autophagy is a major pathway for the elimination of protein aggregates and damaged organelles and therefore contributes to cellular homeostasis. This catabolic process begins with the formation of the double membrane-bound autophagosome that engulfs portions of the cytoplasm and subsequently fuses with a lysosome to form an autolysosome, in which lysosomal enzymes digest autophagic substrates. Defects at various stages of autophagy have been associated with pathological mutations of several ALS-linked genes including SOD1, p62, TDP-43, and optineurin, suggesting that such defects may play a causative role in the pathogenesis of this condition. In this review, we summarize the dysregulation of autophagy associated with ALS as well as potential therapeutic strategies based on modulation of the autophagic process.
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