A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress Research Papers

We report here that C9orf72, which is linked to the most common forms of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), is a key regulator of lipid metabolism under stress. Loss of C9orf72 leads to an overactivation of starvation-induced lipid metabolism that is mediated by dysregulated autophagic digestion of lipids and increased de novo fatty acid synthesis. C9orf72 acts by promoting the lysosomal degradation of coactivator-associated arginine methyltransferase 1 (CARM1), which in turn regulates autophagy–lysosomal functions and lipid metabolism. In ALS/FTD patient-derived neurons or tissues, a reduction in C9orf72 function is associated with dysregulation in the levels of CARM1, fatty acids, and NADPH oxidase NOX2. These results reveal a C9orf72–CARM1 axis in the control of stress-induced lipid metabolism and implicates epigenetic dysregulation in relevant human diseases.
Source: Genes and Development - Category: Genetics & Stem Cells Authors: Tags: Research Papers Source Type: research

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CONCLUSIONS: The varied pharmacological mechanisms of NBP involve many complex molecular mechanisms; however, there many unknown pharmacological effects await further study.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID: 31107716 [PubMed - as supplied by publisher]
Source: Chinese Medical Journal - Category: General Medicine Authors: Tags: Chin Med J (Engl) Source Type: research
In this study, a significant (30%) increase in maximum lifespan of mice was found after nonablative transplantation of 100 million nucleated bone marrow (BM) cells from young donors, initiated at the age that is equivalent to 75 years for humans. Moreover, rejuvenation was accompanied by a high degree of BM chimerism for the nonablative approach. Six months after the transplantation, 28% of recipients' BM cells were of donor origin. The relatively high chimerism efficiency that we found is most likely due to the advanced age of our recipients having a depleted BM pool. In addition to the higher incorporation rates, ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One class of major pathogenic molecules in C9ORF72-ALS/FTD is dipeptide repeat proteins such as poly(GR), whose toxicity has been well documented in cellular and animal models. However, it is...
Source: Proceedings of the National Academy of Sciences - Category: Science Authors: Tags: Biological Sciences Source Type: research
Much of the spectrum of age-related neurodegenerative conditions is associated with, and at least partly caused by, the accumulation of abnormal proteins or protein aggregates in the brain. These include the α-synuclein associated with Parkinson's disease, the amyloid-β and tau of Alzheimer's disease, and so forth. This sort of condition, in which malformed proteins are a contributing cause, is termed a proteopathy. A more recently recognized neurodegenerative proteopathy involves the TDP-43 protein, and the evidence for its relevance to age-related dementia has reached the point at which researchers and adminis...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs
In recent years, there has been a jarring awakening that liquid–liquid phase separation (LLPS) of key protein and nucleic acid scaffolds underpins the biogenesis of diverse membraneless organelles, including P granules and stress granules in the cytoplasm and nucleoli and paraspeckles in the nucleus. These biomolecular condensates are proposed to be critical organizers of subcellular biochemistry and to control the flow of information from genotype to phenotype. Despite clear biological utility, LLPS can also have deleterious outcomes. Phase-separated compartments can concentrate specific RNA-binding proteins (RBPs),...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: JBC Reviews Source Type: research
Conclusion and Perspectives The ARE has been studied for a long time, and about 20 ARE-BPs have been identified since discovery of first ARE-BP, AUF1 (Brewer, 1991; Garcia-Maurino et al., 2017). The specific target mRNAs for different ARE-BPs, as well as their molecular functions on these mRNAs, and contribution of this regulation to specific biological processes are gradually being uncovered. However, with a few exceptions, the molecular mechanisms used by ARE-BPs to regulate their targets are still unknown. In particular, the mechanism to recognize and control specific targets from the large number of transcripts t...
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
Abstract Some neurological disorders, including Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Fragile X Syndrome, Huntington's Disease, Myotonic Dystrophy, and various ataxias, can be caused by expansions of short nucleic acid sequence repeats in specific genes. A possible disease mechanism involves the transcribed repeat RNA binding an RNA-binding protein (RBP), resulting in its sequestration and thus dysfunction. Polycomb Repressive Complex 2 (PRC2), the histone methyltransferase that deposits the H3K27me3 mark of epigenetically silenced chromatin, binds G-rich RNAs and has especially high ...
Source: RNA - Category: Genetics & Stem Cells Authors: Tags: RNA Source Type: research
Abstract Haploinsufficiency of the protein kinase Tbk1 has shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the pathogenic mechanisms are unclear. Here we show that conditional neuronal deletion of Tbk1 in leads to cognitive and locomotor deficits in mice. Tbk1-NKO mice exhibited numerous neuropathological changes, including neurofibrillary tangles, abnormal dendrites, reduced dendritic spine density, and cortical synapse loss. The Purkinje cell layer of the cerebellum presented dendritic swelling, abnormally shaped astrocytes, and p62- and ubiquitin-positive aggr...
Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
HJ Abstract Abnormal accumulation of proteins is a hallmark of a variety of neurological diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Maintenance of protein homeostasis (proteostasis) in neurons via proteasomal and macroautophagy/autophagy-lysosomal degradation is thought to be central for proper neuronal function and survival. We recently reported evolutionarily conserved roles for two ALS-linked proteins, UBQLN2 (ubiquilin 2) and VAPB, in regulation of lysosomal degradation. Ubiquilins are required for v-ATPase-mediated lysosomal acidification, whereas VAPs are requi...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
Aggregates of the RNA-binding protein TDP-43 (TAR DNA-binding protein) are a hallmark of the overlapping neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates. We found that this early oligomerization stage is primarily driven by TDP-43's RNA-binding region...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Neurobiology Source Type: research
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