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

An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study DOI Creative Commons
Timothy M. Miller, Alan Pestronk,

William David

et al.

The Lancet Neurology, Journal Year: 2013, Volume and Issue: 12(5), P. 435 - 442

Published: March 29, 2013

Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the Gly93Ala rat model sclerosis, antisense oligonucleotide ISIS 333611 delivered to CSF decreased mRNA and protein concentrations spinal cord tissue prolonged survival. We aimed assess safety, tolerability, pharmacokinetics after intrathecal administration patients with SOD1-related sclerosis.In this randomised, placebo-controlled, phase 1 trial, we by infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 1·50 3·00 mg) four cohorts eight SOD1-positive sclerosis (six assigned 333611, two placebo each cohort). did randomisation a web-based system, assigning blocks four. Patients investigators were masked treatment assignment. Participants allowed re-enrol subsequent cohorts. Our primary objective was safety tolerability 333611. Assessments done during 28 days infusion. This study registered Clinicaltrials.gov, number NCT01041222.Seven (88%) group versus 20 24 (83%) had adverse events. The most common events post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] 4/24 [17%]), nausea (0/8 [0%] 3/24 [13%]). recorded no dose-limiting toxic effects or any concerns related No serious occurred given Re-enrolment re-treatment also well tolerated.This trial is first clinical delivery oligonucleotide. tolerated when administered as Antisense oligonucleotides CNS might be feasible for neurological disorders.The ALS Association, Muscular Dystrophy Isis Pharmaceuticals.

Language: Английский

Citations

590
Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis DOI

Chi-Hong Wu,

Claudia Fallini, Nicola Ticozzi

et al.

Nature, Journal Year: 2012, Volume and Issue: 488(7412), P. 499 - 503

Published: July 15, 2012

Language: Английский

Citations

581
Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis DOI
Laura Ferraiuolo, Janine Kirby, Andrew J. Grierson

et al.

Nature Reviews Neurology, Journal Year: 2011, Volume and Issue: 7(11), P. 616 - 630

Published: Nov. 1, 2011

Language: Английский

Citations

579
Mitochondria: The Next (Neurode)Generation DOI Creative Commons

Eric A. Schon,

Serge Przedborski

Neuron, Journal Year: 2011, Volume and Issue: 70(6), P. 1033 - 1053

Published: June 1, 2011

Language: Английский

Citations

546
Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis DOI
Phuong H. Nguyen, Ayyalusamy Ramamoorthy, Bikash R. Sahoo

et al.

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

Citations

539
Development of Multifunctional Molecules as Potential Therapeutic Candidates for Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis in the Last Decade DOI
Masha G. Savelieff,

Geewoo Nam,

Juhye Kang

et al.

Chemical Reviews, Journal Year: 2018, Volume and Issue: 119(2), P. 1221 - 1322

Published: Aug. 10, 2018

Neurodegenerative diseases pose a substantial socioeconomic burden on society. Unfortunately, the aging world population and lack of effective cures foreshadow negative outlook. Although large amount research has been dedicated to elucidating pathologies neurodegenerative diseases, their principal causes remain elusive. Metal ion dyshomeostasis, proteopathy, oxidative stress, neurotransmitter deficiencies are pathological features shared across multiple disorders. In addition, these factors proposed be interrelated upon disease progression. Thus, development multifunctional compounds capable simultaneously interacting with several components suggested as solution undertake complex diseases. this review, we outline discuss possible therapeutic targets in Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis molecules, previously designed or discovered potential drug candidates for disorders emphasis multifunctionality. underrepresented areas discussed indicate new directions.

Language: Английский

Citations

482
The role of mitochondria in amyotrophic lateral sclerosis DOI Creative Commons

Emma F. Smith,

Pamela J. Shaw, Kurt J. De Vos

et al.

Neuroscience Letters, Journal Year: 2017, Volume and Issue: 710, P. 132933 - 132933

Published: June 30, 2017

Mitochondria are unique organelles that essential for a variety of cellular processes including energy metabolism, calcium homeostasis, lipid biosynthesis, and apoptosis. Mitochondrial dysfunction is prevalent feature many neurodegenerative diseases motor neuron disorders such as amyotrophic lateral sclerosis (ALS). Disruption mitochondrial structure, dynamics, bioenergetics buffering has been extensively reported in ALS patients model systems suggested to be directly involved disease pathogenesis. Here we review the alterations parameters examine common pathways dysfunction.

Language: Английский

Citations

476
Biological metals and metal-targeting compounds in major neurodegenerative diseases DOI Creative Commons
Kevin J. Barnham, Ashley I. Bush

Chemical Society Reviews, Journal Year: 2014, Volume and Issue: 43(19), P. 6727 - 6749

Published: Jan. 1, 2014

Metals are functionally essential, but redistribute in neurodegenerative disease where they induce protein aggregates, catalyze radical formation, and lose bioavailability.

Language: Английский

Citations

444
C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking DOI

Manal A. Farg,

Vinod Sundaramoorthy,

Jessica M. Sultana

et al.

Human Molecular Genetics, Journal Year: 2014, Volume and Issue: 23(13), P. 3579 - 3595

Published: Feb. 18, 2014

Intronic expansion of a hexanucleotide GGGGCC repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene is major cause familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. However, cellular function C9ORF72 protein remains unknown. Here, we demonstrate that regulates endosomal trafficking. colocalized with Rab proteins implicated autophagy endocytic transport: Rab1, Rab5, Rab7 Rab11 neuronal cell lines, primary cortical neurons human spinal cord motor neurons, consistent previous predictions bears guanine exchange factor activity. Consistent this notion, was present extracellular space as cytoplasmic vesicles. Depletion using siRNA inhibited transport Shiga toxin from plasma membrane to Golgi apparatus, internalization TrkB receptor altered ratio autophagosome marker light chain 3 (LC3) II:LC3I, indicating endocytosis autophagy. also ubiquilin-2 LC3-positive vesicles, co-migrated lysosome-stained vesicles providing further evidence Investigation interacting mass spectrometry identified other ALS; heterogeneous nuclear ribonucleoproteins, hnRNPA2/B1 hnRNPA1, actin. Treatment cells overexpressing proteasome inhibitors induced formation stress granules positive for hnRNPA1 hnRNPA2/B1. Immunohistochemistry ALS patient revealed increased colocalization between compared controls, suggesting possible dysregulation trafficking patients bearing expansion. Hence, study identifies role Rab-mediated

Language: Английский

Citations

441
Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases DOI Open Access
Nurbubu T. Moldogazieva, Innokenty M. Mokhosoev, Tatiana I. Melnikova

et al.

Oxidative Medicine and Cellular Longevity, Journal Year: 2019, Volume and Issue: 2019, P. 1 - 14

Published: Aug. 14, 2019

Oxidative stress is a consequence of the use oxygen in aerobic respiration by living organisms and denoted as persistent condition an imbalance between generation reactive species (ROS) ability endogenous antioxidant system (AOS) to detoxify them. The oxidative theory has been confirmed many animal studies, which demonstrated that maintenance cellular homeostasis biomolecular stability integrity crucial for longevity successful aging. Mitochondrial dysfunction, impaired protein (proteostasis) network, alteration activities transcription factors such Nrf2 NF- κ B, disturbances quality control machinery includes molecular chaperones, ubiquitin-proteasome (UPS), autophagy/lysosome pathway have observed during aging age-related chronic diseases. accumulation ROS under conditions results induction lipid peroxidation glycoxidation reactions, leads elevated production aldehydes their derivatives glyoxal, methylglyoxal (MG), malonic dialdehyde (MDA), 4-hydroxy-2-nonenal (HNE) giving rise advanced lipoxidation glycation end products (ALEs AGEs, respectively). Both ALEs AGEs play key roles response stimuli through regulation variety cell signaling pathways. However, ALE AGE cross-linking aggregation resulting functioning causes damage death. This implicated various pathologies inflammation, neurodegenerative diseases, atherosclerosis, vascular complications diabetes mellitus. In present review, we discuss experimental data evidencing impairment functions caused AGE/ALE conditions. We focused on implications ALEs/AGEs diseases demonstrate identification dysfunctions involved disease initiation progression can serve basis discovery relevant therapeutic agents.

Language: Английский

Citations

403