RNA metabolism in ALS: When normal processes become pathological

Droppelmann, Cristian A.; Campos-Melo, Danae; Ishtiaq, Muhammad; Volkening, Kathryn; Strong, Michael J.

doi:10.3109/21678421.2014.881377

Cited by 53 publications

(36 citation statements)

References 209 publications

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“…The pathogenic mechanism associated with FUS/TLS is tightly associated with TDP-43 because of its similar roles in RNA metabolism. Therefore, FUS/ALS pathogenesis could be also related to a misregulation of its function associated with its role in stress granule formation and function, and alterations on post-translational modifications of the protein (Droppelmann et al 2014;Strong and Volkening 2011).…”

Section: Fus/tlsmentioning

confidence: 97%

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RNA-binding proteins as molecular links between cancer and neurodegeneration

et al. 2014

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For many years, epidemiological studies have suggested an association between cancer and neurodegenerative disorders-two disease processes that seemingly have little in common. Although these two disease processes share disruptions in a wide range of cellular pathways, including cell survival, cell death and the cell cycle, the end result is very divergent: uncontrolled cell survival and proliferation in cancer and progressive neuronal cell death in neurodegeneration. Despite the clinical data connecting these two disease processes, little is known about the molecular links between them. Among the mechanisms affected in cancer and neurodegenerative diseases, alterations in RNA metabolism are obtaining significant attention given the critical role for RNA transcription, maturation, transport, stability, degradation and translation in normal cellular function. RNA-binding proteins (RBPs) are integral to each stage of RNA metabolism through their participation in the formation of ribonucleoprotein complexes (RNPs). RBPs have a broad range of functions including posttranscriptional regulation of mRNA stability, splicing, editing and translation, mRNA export and localization, mRNA polyadenylation and miRNA biogenesis, ultimately impacting the expression of every single gene in the cell. In this review, we examine the evidence for RBPs as being key a molecular linkages between cancer and neurodegeneration.

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Section: Fus/tlsmentioning

confidence: 97%

“…SGs are key cellular structures formed to facilitate cell survival by translational arrest of non-essential transcripts and by sequestering pro-apoptotic proteins during cellular stress. Therefore, dysregulation of SGs could be associated with cytoplasmic inclusion formation and neuronal death (Droppelmann et al 2014;Strong and Volkening 2011).…”

Section: Tdp-43mentioning

confidence: 99%

RNA-binding proteins as molecular links between cancer and neurodegeneration

et al. 2014

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“…Several lines of evidence illustrate how aberrant RNA processing due to changes in TDP-43, FUS, and/or C9ORF72 may directly play a role in the pathogenesis of both fALS and sALS (Droppelmann et al, 2014; Raman et al, 2014). Mutations in the TDP-43, FUS and C9ORF72 genes have been shown to alter normal RNA processing which may, in turn, affect important protein homeostasis causing (detrimental) changes in neuronal function (Polymenidou et al, 2012; Ling et al, 2013).…”

Section: Theories On the Cause(s) Of Salsmentioning

confidence: 99%

ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

2014

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Amyotrophic Lateral Sclerosis (ALS) is being redefined as a distal axonopathy, in that many molecular changes influencing motor neuron degeneration occur at the neuromuscular junction (NMJ) at very early stages of the disease prior to symptom onset. A huge variety of genetic and environmental causes have been associated with ALS, and interestingly, although the cause of the disease can differ, both sporadic and familial forms of ALS show a remarkable similarity in terms of disease progression and clinical manifestation. The NMJ is a highly specialized synapse, allowing for controlled signaling between muscle and nerve necessary for skeletal muscle function. In this review we will evaluate the clinical, animal experimental and cellular/molecular evidence that supports the idea of ALS as a distal axonopathy. We will discuss the early molecular mechanisms that occur at the NMJ, which alter the functional abilities of the NMJ. Specifically, we focus on the role of axon guidance molecules on the stability of the cytoskeleton and how these molecules may directly influence the cells of the NMJ in a way that may initiate or facilitate the dismantling of the neuromuscular synapse in the presymptomatic stages of ALS.

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“…The lack of treatments that fundamentally alter the disease course is in part related to the confounding array of disturbed cellular processes in ALS. However, there is increasing consensus that perturbations in RNA metabolism are critical to the disease process (Strong, 2010; Droppelmann et al, 2014). …”

Section: Dbl-homology Gefs In the Pathogenesis Of Alsmentioning

confidence: 99%

The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases

Droppelmann

Campos-Melo

Volkening

et al. 2014

Front. Cell. Neurosci.

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Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl-related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3′ untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.

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RNA metabolism in ALS: When normal processes become pathological

Cited by 53 publications

References 209 publications

RNA-binding proteins as molecular links between cancer and neurodegeneration

RNA-binding proteins as molecular links between cancer and neurodegeneration

ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease

The emerging role of guanine nucleotide exchange factors in ALS and other neurodegenerative diseases

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