Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis

Ling, Shuo-Chien; Polymenidou, Magdalini; Cleveland, Don W.

doi:10.1016/j.neuron.2013.07.033

Cited by 1,505 publications

(1,703 citation statements)

References 259 publications

(394 reference statements)

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“…Interestingly, 7/44 identified SEs are within genes involved in the ubiquitin proteasome pathway, including five E3 Ubiquitin ligases: Herc2 , Ube3c , Wwp1 , Ttc3 and Wsb1 . Overall, these data raise the question of whether these events have the potential to alter CNS proteostasis, a central mechanism involved in neurodegeneration (Ling et al , 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Despite this, the mechanism(s) by which TDP‐43 mutations lead to disease remains unknown, and both nuclear loss of function (LOF) and cytoplasmic gain of function (GOF) have been proposed to play a role (Ling et al , 2013). TDP‐43 deposition and nuclear depletion in post‐mortem tissue support a potential role for LOF in end‐stage ALS.…”

Section: Introductionmentioning

confidence: 99%

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Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

et al. 2018

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TDP‐43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP‐43 function at physiological levels both in vitro and in vivo. Interestingly, we find that mutations within the C‐terminal domain of TDP‐43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP‐43 loss‐ and gain‐of‐function effects. TDP‐43 gain‐of‐function effects in these mice reveal a novel category of splicing events controlled by TDP‐43, referred to as “skiptic” exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain‐of‐function mutation in endogenous Tardbp causes an adult‐onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain‐of‐function and skiptic exons in ALS patient‐derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP‐43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

et al. 2018

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“…These proteins shuttle between the nucleus and cytoplasm and have multiple roles in RNA metabolism, including transcription, splicing, and mRNA transport. In addition, all of these factors, as well as SMN, have been found in cytoplasmic stress granules, dynamic sites of translational repression that form rapidly during cellular stress (62,63). A hallmark of ALS pathology is the appearance of cytoplasmic ubiquitinated aggregates of TDP-43 in the brain and spinal cord.…”

Section: Discussionmentioning

confidence: 99%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

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“…neurodegeneration | motor neurons | amyotrophic lateral sclerosis | electrophysiology A myotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive and usually lethal neurodegenerative condition prominently featuring loss of motor neurons (MNs) and muscle denervation (1)(2)(3). Inherited forms of ALS, accounting for ∼10% of cases, potentially inform about disease mechanisms, including: protein folding and quality control [e.g., mutant superoxide dismutase 1 (SOD1), ubiquilin2, and VCP]; RNA binding proteins (e.g., TDP43, FUS, and HNRNPA1); or a DNA expansion (C9ORF72 hexanucleotide expansion).…”

mentioning

confidence: 99%

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

Hadzipasic

Tahvildari

Nagy

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) affects motor neurons (MNs) in the brain and spinal cord. Understanding the pathophysiology of this condition seems crucial for therapeutic design, yet few electrophysiological studies in actively degenerating animal models have been reported. Here, we report a novel preparation of acute slices from adult mouse spinal cord, allowing visualized whole cell patch-clamp recordings of fluorescent lumbar MN cell bodies from ChAT-eGFP or superoxide dismutase 1-yellow fluorescent protein (SOD1YFP) transgenic animals up to 6 mo of age. We examined 11 intrinsic electrophysiologic properties of adult ChAT-eGFP mouse MNs and classified them into four subtypes based on these parameters. The subtypes could be principally correlated with instantaneous (initial) and steady-state firing rates. We used retrograde tracing using fluorescent dye injected into fast or slow twitch lower extremity muscle with slice recordings from the fluorescent-labeled lumbar MN cell bodies to establish that fast and slow firing MNs are connected with fast and slow twitch muscle, respectively. In a G85R SOD1YFP transgenic mouse model of ALS, which becomes paralyzed by 5-6 mo, where MN cell bodies are fluorescent, enabling the same type of recording from spinal cord tissue slices, we observed that all four MN subtypes were present at 2 mo of age. At 4 mo, by which time substantial neuronal SOD1YFP aggregation and cell loss has occurred and symptoms have developed, one of the fast firing subtypes that innvervates fast twitch muscle was lost. These results begin to describe an order of the pathophysiologic events in ALS.neurodegeneration | motor neurons | amyotrophic lateral sclerosis | electrophysiology A myotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive and usually lethal neurodegenerative condition prominently featuring loss of motor neurons (MNs) and muscle denervation (1-3). Inherited forms of ALS, accounting for ∼10% of cases, potentially inform about disease mechanisms, including: protein folding and quality control [e.g., mutant superoxide dismutase 1 (SOD1), ubiquilin2, and VCP]; RNA binding proteins (e.g., TDP43, FUS, and HNRNPA1); or a DNA expansion (C9ORF72 hexanucleotide expansion). The clinical courses of the various heritable forms and the 90% of cases that are considered sporadic are not distinct, however, reflecting a potentially shared progressive loss of MNs and motor circuit dysfunction (4).ALS has been modeled in mice that are transgenic for a variety of mutant forms of SOD1, allowing for the study of the trajectory of the condition at various time points (5, 6). Among the studies conducted to date are a number addressing electrophysiological changes. From these studies, however, there does not appear to be a clear consensus on the changes that occur in MNs before and during the development of symptoms (7). For example, whereas research on the neuromuscular junction has revealed preferential denervation of fast twitch (type IIb) muscle fibers (8-10), t...

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Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis

Cited by 1,505 publications

References 259 publications

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

Mice with endogenous TDP ‐43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS

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