Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons DOI Open Access
Karen Castillo, Melissa Nassif,

Vicente Valenzuela

et al.

Autophagy, Journal Year: 2013, Volume and Issue: 9(9), P. 1308 - 1320

Published: Sept. 3, 2013

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, pathological hallmark ALS. Autophagy the major degradation pathway involved in clearance damaged organelles and aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant cell culture models, several studies suggest that impairment may also contribute pathogenesis. In this report, we tested potential use trehalose, disaccharide induces MTOR-independent autophagy, development experimental Administration trehalose SOD1 transgenic mice significantly prolonged life span attenuated progression signs. These effects were associated decreased accumulation aggregates enhanced survival. The protective increased levels motoneurons. Cell experiments demonstrated led by NSC34 cells protected primary motoneurons against toxicity conditioned media from astrocytes. At mechanistic level, treatment significant upregulation expression key autophagy-related genes at mRNA level including Lc3, Becn1, Sqstm1 Atg5. Consistent these changes, administration nuclear translocation FOXO1, an important transcription factor activation neurons. This study suggests enhancers for

Language: Английский

Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms DOI Open Access

Leslie I. Grad,

Justin J. Yerbury, Bradley J. Turner

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2014, Volume and Issue: 111(9), P. 3620 - 3625

Published: Feb. 18, 2014

Significance Amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease, is associated with mutation and misfolding of the Cu/Zn superoxide dismutase (SOD1) protein. Prior studies found that mutant misfolded SOD1 can convert wild-type (WT) to a form inside living cells in prion-like fashion. We now report WT be transmitted from cell cell, propagated protein perpetuated. Misfolded transmission between mediated through release uptake aggregates or via small membrane-bounded transport vesicles called exosomes. These mechanisms may help explain why sporadic ALS, without known genetic cause, spread systematically region progressive manner.

Language: Английский

Citations

393
The genetics and neuropathology of amyotrophic lateral sclerosis DOI
Ammar Al‐Chalabi, Ashley Jones, Claire Troakes

et al.

Acta Neuropathologica, Journal Year: 2012, Volume and Issue: 124(3), P. 339 - 352

Published: Aug. 1, 2012

Language: Английский

Citations

382
Necroptosis Drives Motor Neuron Death in Models of Both Sporadic and Familial ALS DOI Creative Commons
Diane B. Ré,

Virginia Le Verche,

Changhao Yu

et al.

Neuron, Journal Year: 2014, Volume and Issue: 81(5), P. 1001 - 1008

Published: Feb. 6, 2014

Language: Английский

Citations

379
The Seeds of Neurodegeneration: Prion-like Spreading in ALS DOI Creative Commons
Magdalini Polymenidou, Don W. Cleveland

Cell, Journal Year: 2011, Volume and Issue: 147(3), P. 498 - 508

Published: Oct. 1, 2011

Misfolded proteins accumulating in several neurodegenerative diseases (including Alzheimer, Parkinson, and Huntington diseases) can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction pathogenic conformation onto its cellular isoform. Evidence for such prion-like has now spread main misfolded proteins, SOD1 TDP-43, implicated amyotrophic lateral sclerosis (ALS). The major may therefore have mechanistic parallels non-cell-autonomous disease within nervous system.

Language: Английский

Citations

356
Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons DOI Open Access
Karen Castillo, Melissa Nassif,

Vicente Valenzuela

et al.

Autophagy, Journal Year: 2013, Volume and Issue: 9(9), P. 1308 - 1320

Published: Sept. 3, 2013

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, pathological hallmark ALS. Autophagy the major degradation pathway involved in clearance damaged organelles and aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant cell culture models, several studies suggest that impairment may also contribute pathogenesis. In this report, we tested potential use trehalose, disaccharide induces MTOR-independent autophagy, development experimental Administration trehalose SOD1 transgenic mice significantly prolonged life span attenuated progression signs. These effects were associated decreased accumulation aggregates enhanced survival. The protective increased levels motoneurons. Cell experiments demonstrated led by NSC34 cells protected primary motoneurons against toxicity conditioned media from astrocytes. At mechanistic level, treatment significant upregulation expression key autophagy-related genes at mRNA level including Lc3, Becn1, Sqstm1 Atg5. Consistent these changes, administration nuclear translocation FOXO1, an important transcription factor activation neurons. This study suggests enhancers for

Language: Английский

Citations

327