Genome wide analysis reveals heparan sulfate epimerase modulates TDP-43 proteinopathy

by Nicole F. Liachko, Aleen D. Saxton, Pamela J. McMillan, Timothy J. Strovas, C. Dirk Keene, Thomas D. Bird, Brian C. Kraemer Pathological phosphorylated TDP-43 protein (pTDP) deposition drives neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the cellular and genetic mechanisms at work in pathological TDP-43 toxicity are not fully elucidated. To identify genetic modifiers of TDP-43 neurotoxicity, we utilized aCaenorhabditis elegans model of TDP-43 proteinopathy expressing human mutant TDP-43 pan-neuronally (TDP-43 tg). In TDP-43 tgC.elegans, we conducted a genome-wide RNAi screen covering 16,767C.elegans genes for loss of function genetic suppressors of TDP-43-driven motor dysfunction. We identified 46 candidate genes that when knocked down partially ameliorate TDP-43 related phenotypes; 24 of these candidate genes have conserved homologs in the human genome. To rigorously validate the RNAi findings, we crossed the TDP-43 transgene into the background of homozygous strong genetic loss of function mutations. We have confirmed 9 of the 24 candidate genes significantly modulate TDP-43 transgenic phenotypes. Among the validated genes we focused on, one of the most consistent genetic modifier genes protecting against pTDP accumulation and motor deficits was the heparan sulfate-modifying enzymehse-5, theC.elegans homolog of glucuronic acid epimerase (GLCE). We found that knockdown of humanGLCE in cultured human ce...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research

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We examined whether Rhy promotes this regulation in bone marrow human mesenchymal stromal cells (BM-hMSCs). Results revealed (i) Rhy modulated biological activity by regulating the mitochondria, N-methyl-D-aspartate receptor subunit, and levels of FGFβ (basic fibroblast growth factor), BDNF (brain-derived neurotrophic factor), OXTR (oxytocin receptor) and ATP (Adenosine triphosphate); (ii) Rhy altered expression level of BM-MSC proliferation/differentiation-related transcription genes; and (iii) interestingly, Rhy amplified the glycolytic flow ratio and lactate dehydrogenase activity while reducing pyruvate dehydrogen...
Source: Cytotherapy - Category: Cytology Source Type: research
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death, with a median survival of 3-5 years and affecting all populations with a rise among Hispanics. ALS patients are mostly cared for by family caregivers (FCGs). FCGs often experience burden, high depression rates, psychological distress and impaired quality-of-life. Also, FCGs may not be able to leave their homes to access resources. Social media might be a way to accessing support, but little is known about quality and quantity of ALS FCGs ’ resources.
Source: Journal of Pain and Symptom Management - Category: Palliative Care Authors: Source Type: research
c Šket The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key r...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
AbstractPrion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multip...
Source: Molecular Neurobiology - Category: Neurology Source Type: research
Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due t...
Source: Cerebrospinal Fluid Research - Category: Neurology Authors: Tags: Research Source Type: research
AbstractAmyotrophic lateral sclerosis (ALS) is a devastating motoneuron (Mn) disease without effective cure currently available. Death of MNs in ALS is preceded by failure of neuromuscular junctions and axonal retraction. Neuregulin 1 (NRG1) is a neurotrophic factor highly expressed in MNs and neuromuscular junctions that support axonal and neuromuscular development and maintenance. NRG1 and its ErbB receptors are involved in ALS. Reduced NRG1 expression has been found in ALS patients and in the ALS SOD1G93A mouse model; however, the expression of the isoforms of NRG1 and its receptors is still controversial. Due to the re...
Source: Neurotherapeutics - Category: Neurology Source Type: research
ConclusionWhile our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about   the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states.
Source: Fluids and Barriers of the CNS - Category: Neuroscience Source Type: research
Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein, is a pathological signature of amyotrophic lateral sclerosis (ALS). Missense mutations in the TARDBP gene are also found in...
Source: Molecular Brain - Category: Neuroscience Authors: Tags: Micro report Source Type: research
This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free." Commentary on Recent Evidence for Cognitive Decline to Precede Amyloid Aggregation in Alzheimer's Disease https://www.fightaging.org/archives/2020/01/commentary-on-recent-evidence-for-cognitive-decline-to-precede-amyloid-aggregation-in-alzheimers-disease/ I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Authors: Mahoney CJ, Kiernan MC PMID: 31944304 [PubMed - as supplied by publisher]
Source: Medical Journal of Australia - Category: General Medicine Tags: Med J Aust Source Type: research
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