Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

Polito, Vinicia Assunta; Li, Hongmei; Martini‐Stoica, Heidi; Wang, Baiping; Li, Yang; Xu, Yin; Swartzlander, Daniel B.; Palmieri, Michela; Ronza, Alberto di; Lee, Virginia M.‐Y.; Sardiello, Marco; Ballabio, Andrea; Zheng, Hui

doi:10.15252/emmm.201303671

Cited by 316 publications

(320 citation statements)

References 61 publications

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“…We have recently shown that trehalose activates TFEB through inhibition of AKT, a negative regulator of TFEB [64]. A growing body of evidence shows that TFEB-mediated enhancement of clearance via lysosomal biogenesis and increased autophagic flux counteracts the accumulation of different proteinaceous materials and slows disease progression in various animal models of disease [21–25,37,65]. Notably, in these studies, clearance of the abnormally accumulated material exerts protective effects against neuronal death, regardless of the nature of the stored material and the pathway by which it would normally be degraded.…”

Section: Discussionmentioning

confidence: 99%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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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

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Section: Discussionmentioning

confidence: 99%

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

et al. 2018

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“…Similarly, inducing TFEB activity in cellular and animal models of Hungtington's disease can reduce protein aggregation and improves neurological functions (Sardiello et al, 2009;Tsunemi et al, 2012). Furthermore, TFEB overexpression or its pharmacological activation in cellular and mouse models of Alzheimer's disease and other tauopathies can also reduce the amount of protein aggregates (Chauhan et al, 2015;Polito et al, 2014;Xiao et al, 2014Xiao et al, , 2015, which results in a reduction of neurodegeneration and improvement of behavioral deficits. Therefore, promotion of intracellular clearance through the induction of TFEB activity might represent a common therapeutic strategy for neurodegenerative disorders.…”

Section: Tfeb As a Therapeutic Target For Diseasesmentioning

confidence: 99%

TFEB at a glance

Napolitano

Ballabio

2016

Journal of Cell Science

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The transcription factor EB (TFEB) plays a pivotal role in the regulation of basic cellular processes, such as lysosomal biogenesis and autophagy. The subcellular localization and activity of TFEB are regulated by mechanistic target of rapamycin (mTOR)-mediated phosphorylation, which occurs at the lysosomal surface. Phosphorylated TFEB is retained in the cytoplasm, whereas dephosphorylated TFEB translocates to the nucleus to induce the transcription of target genes. Thus, a lysosome-to-nucleus signaling pathway regulates cellular energy metabolism through TFEB. Recently, in vivo studies have revealed that TFEB is also involved in physiological processes, such as lipid catabolism. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of murine models of disease, such as Parkinson's and Alzheimer's, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. In this Cell Science at a Glance article and accompanying poster, we present an overview of the latest research on TFEB function and its implication in human diseases.

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“…TFEB is able to reduce neurofibrillary tangle pathology, rescue behavioral and synaptic deficits, and effectively compensate for neurodegeneration in the rTg4510 mouse model of autopathy. 109 Based on these studies, Stern et al 107 proposed that autophagy and lysosomal dysfunction may be emerging mechanisms of NM toxicity (ie, NP-mediated lysosome-dependent autophagy). Autophagy can play dual roles in cell survival after interaction with NPs: autophagy can play a cytoprotective role or a cytotoxic role under different conditions.…”

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confidence: 99%

Central nervous system toxicity of metallic nanoparticles

Feng¹,

Chen²,

Zhang³

et al. 2015

IJN

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Nanomaterials (NMs) are increasingly used for the therapy, diagnosis, and monitoring of disease- or drug-induced mechanisms in the human biological system. In view of their small size, after certain modifications, NMs have the capacity to bypass or cross the blood–brain barrier. Nanotechnology is particularly advantageous in the field of neurology. Examples may include the utilization of nanoparticle (NP)-based drug carriers to readily cross the blood–brain barrier to treat central nervous system (CNS) diseases, nanoscaffolds for axonal regeneration, nanoelectromechanical systems in neurological operations, and NPs in molecular imaging and CNS imaging. However, NPs can also be potentially hazardous to the CNS in terms of nano-neurotoxicity via several possible mechanisms, such as oxidative stress, autophagy, and lysosome dysfunction, and the activation of certain signaling pathways. In this review, we discuss the dual effect of NMs on the CNS and the mechanisms involved. The limitations of the current research are also discussed.

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Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

Cited by 316 publications

References 61 publications

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

TFEB at a glance

Central nervous system toxicity of metallic nanoparticles

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