Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada, Sami J.

doi:10.1007/s13311-015-0340-3

Cited by 33 publications

(22 citation statements)

References 158 publications

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“…Because TDP-43 is found in co-aggregates with FUS in ALS [17], we sought to determine if FUS was also affected by DUX4-FL expression. We found that FUS nuclear aggregates were induced by expression of DUX4-FL, either exogenously from a BacMam vector (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nuclear speckles that contain the SC35 protein include pre-mRNA splicing factors, and transcription sites for specific genes localize near SC35 speckles in myonuclei [16]. Additional gene regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, mutations of which have been linked to pathogenesis in some cases of amyotrophic lateral sclerosis (ALS) [17]. …”

Section: Introductionmentioning

confidence: 99%

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Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4

Homma

Beermann

et al. 2016

Skeletal Muscle

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BackgroundNuclear bodies, such as nucleoli, PML bodies, and SC35 speckles, are dynamic sub-nuclear structures that regulate multiple genetic and epigenetic processes. Additional regulation is provided by RNA/DNA handling proteins, notably TDP-43 and FUS, which have been linked to ALS pathology. Previous work showed that mouse cell line myotubes have fewer but larger nucleoli than myoblasts, and we had found that nuclear aggregation of TDP-43 in human myotubes was induced by expression of DUX4-FL, a transcription factor that is aberrantly expressed and causes pathology in facioscapulohumeral dystrophy (FSHD). However, questions remained about nuclear bodies in human myogenesis and in muscle disease.MethodsWe examined nucleoli, PML bodies, SC35 speckles, TDP-43, and FUS in myoblasts and myotubes derived from healthy donors and from patients with FSHD, laminin-alpha-2-deficiency (MDC1A), and alpha-sarcoglycan-deficiency (LGMD2D). We further examined how these nuclear bodies and proteins were affected by DUX4-FL expression.ResultsWe found that nucleoli, PML bodies, and SC35 speckles reorganized during differentiation in vitro, with all three becoming less abundant in myotube vs. myoblast nuclei. In addition, though PML bodies did not change in size, both nucleoli and SC35 speckles were larger in myotube than myoblast nuclei. Similar patterns of nuclear body reorganization occurred in healthy control, MDC1A, and LGMD2D cultures, as well as in the large fraction of nuclei that did not show DUX4-FL expression in FSHD cultures. In contrast, nuclei that expressed endogenous or exogenous DUX4-FL, though retaining normal nucleoli, showed disrupted morphology of some PML bodies and most SC35 speckles and also co-aggregation of FUS with TDP-43.ConclusionsNucleoli, PML bodies, and SC35 speckles reorganize during human myotube formation in vitro. These nuclear body reorganizations are likely needed to carry out the distinct gene transcription and splicing patterns that are induced upon myotube formation. DUX4-FL-induced disruption of some PML bodies and most SC35 speckles, along with co-aggregation of TDP-43 and FUS, could contribute to pathogenesis in FSHD, perhaps by locally interfering with genetic and epigenetic regulation of gene expression in the small subset of nuclei that express high levels of DUX4-FL at any one time.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4

Homma

Beermann

et al. 2016

Skeletal Muscle

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“…Intriguing clues have come from genetic mutations that cause such diseases to recur sporadically in pedigrees, even though familial cases typically comprise only a small fraction of the total (Lio et al ., 2003; Cardenas et al ., 2012; Abdel‐Salam, 2014; Barmada, 2015; Heneka et al ., 2015). Those mutations may render a single ‘seed’ protein susceptible to aggregation in whichever brain regions it is chiefly expressed.…”

Section: Introductionmentioning

confidence: 99%

“…Protein aggregation has long been recognized as a common feature of most or all age-dependent neurodegenerative diseases, and yet very little is known about which features of aggregating proteins contribute to their accrual or their neurotoxicity. Intriguing clues have come from genetic mutations that cause such diseases to recur sporadically in pedigrees, even though familial cases typically comprise only a small fraction of the total (Lio et al, 2003;Cardenas et al, 2012;Abdel-Salam, 2014;Barmada, 2015;Heneka et al, 2015). Those mutations may render a single 'seed' protein susceptible to aggregation in whichever brain regions it is chiefly expressed.…”

Section: Introductionmentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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“…In the article by CooperKnock et al [4], we hear about the advances gained from the discovery of the recent identification of a hexanucleotide repeat expansion in C9orf72, and the authors emphasize the associated phenotypes, proposed disease mechanisms related to the repeat expansion, similarities to other disorders with repeat expansions, premise for genetic screening, and most promising therapeutic developments. Dr. Sami Barmada [5] then discusses data supporting a converging mechanism in ALS centered on RNA dysregulation, presenting the current evidence depicting abnormalities in RNA processing and metabolism, mislocalization or aggregation of RNA binding proteins, and mutations in RNA processing enzymes. He also identifies potential therapeutic targets based on these mechanisms that may foster novel treatment strategies.…”

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confidence: 99%

The Spectrum of Motor Neuron Diseases: From Childhood Spinal Muscular Atrophy to Adult Amyotrophic Lateral Sclerosis

Sakowski

Feldman

2015

Neurotherapeutics

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Since the topic of motor neuron diseases was last covered in Neurotherapeutics in 2008, increasing insight into genetic causes and underlying disease mechanisms has fueled several advances that have paved the way for new therapeutic strategies that are currently in development or being tested in clinical trials. In this special issue, we present reviews by leading investigators in the field that detail these advances for spinal muscular atrophy (SMA), an inherited neuromuscular disease associated with motor neuron degeneration and muscle atrophy that presents early in life, and amyotrophic lateral sclerosis (ALS), a fatal adult-onset neuromuscular disease also characterized by loss of motor neurons. The papers are divided into 4 main sections that cover 1) SMA advances, 2) ALS challenges and recent biological advances, 3) ALS clinical trial design considerations and outcome measures, and 4) emerging ALS treatments. Together, these articles offer a timely and comprehensive look into the recent research advances, current clinical considerations, and therapeutic prospects currently in development or being tested for motor neuron diseases.The issue begins with 2 papers focused on SMA. In the first article, Drs. Michelle Farrar and Matthew Kiernan [1] provide a detailed overview of the genetic basis of SMA forms and variants and present common pathophysiological mechanisms, including discussion of the function of the survival motor neuron protein. They then discuss considerations for therapeutic development and testing before reviewing potential molecular biomarkers for outcome assessments and trial design. Next, Drs. Constantin d'Ydewalle and Charlotte Sumner [2] present an eloquent synopsis of promising SMA treatments currently in advanced stages of development, a discussion that is prefaced by an overview of the available in vivo mouse SMA models. The treatment strategies include some originally designed for applications in ALS, approaches to induce survival motor neuron, and new treatment paradigms harnessing epigenetic targets, antisense oligonucleotides, and gene therapy approaches. Notably, both articles also discuss important issues that remain to be addressed for current progress, such as how well preclinical models recapitulate the human phenotype, how to factor in disease heterogeneity and identify and define potential therapeutic windows, and how to best analyze effects on disease progression. We believe the recent novel insights and current advances bode well for continued progress and the identification of much needed treatment options in SMA.The second section of the issue begins with a review by Drs. Jeffrey Rosenfeld and Michael Strong [3], which specifies the current challenges underlying therapeutic development that accompany the recent expansions in our understanding of the complex, multifaceted nature of ALS. Briefly, establishing firm diagnostic and prognostic criteria, determining what role frontotemporal dysfunction plays in the classification of ALS, identifying an accepted biomarker, determi...

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Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Cited by 33 publications

References 158 publications

Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4

Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

The Spectrum of Motor Neuron Diseases: From Childhood Spinal Muscular Atrophy to Adult Amyotrophic Lateral Sclerosis

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