ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

Klim, Joseph R.; Williams, Luis A.; Limone, Francesco; Juan, Irune Guerra San; Davis‐Dusenbery, Brandi N.; Mordes, Daniel A.; Burberry, Aaron; Steinbaugh, Michael J.; Gamage, Kanchana K.; Kirchner, Rory; Moccia, Rob; Cassel, Seth H.; Chen, Kuchuan; Wainger, Brian J.; Woolf, Clifford J.; Eggan, Kevin

doi:10.1038/s41593-018-0300-4

Cited by 434 publications

(685 citation statements)

References 64 publications

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“…Similarly, examination of downregulated genes overlapping among the Blue and Midnightblue modules in data set A, the Darkgreen module in data set B, and MNs highlighted genes previously implicated in ALS (Lederer et al, 2007;Saris et al, 2009;Umahara et al, 2016) ( Figure 5D). The GO term regulation of neuronal projection development was significantly represented among the overlapping, downregulated genes ( Figure 5D), consistent with recent models suggesting that deficiencies in maintaining axonal projections may underlie ALS (Klim et al, 2019;Melamed et al, 2019).…”

Section: Als Ipsc-mn Cultures Exhibit Transcriptional Changes Detectasupporting

confidence: 88%

“…The most recent iPSC-based transcriptomic reports performed RNA profiling at time points during differentiation concomitant with various observed ALS phenotypes which include nuclear RNA foci (Sareen et al, 2013), decreased neurite length (Fujimori et al, 2018), reduced neurite repair after injury (Klim et al, 2019;Melamed et al, 2019), and MN death (Kiskinis et al, 2014;Shi et al, 2018). Several of these protocols differentiated iPSCs for over 30 days, and many required a relatively prolonged maturation phase, the presence of glia, and additional stressor conditions in order to yield a disease phenotype.…”

Section: Single-cell Analysis Enables Attribution Of Early and Convermentioning

confidence: 99%

“…Of note, recent literature has characterized convergent and divergent aspects of ALS pathways and mechanisms across subject lines and subsets of ALS conditions, often delineated by genotype (including familial ALS mutations in C9orf72, SOD1, hnRNPA1, TARDBP, FUS, and CHMP2B as well as sporadic ALS), site of symptom onset, disease progression, or treatment response (Chen et al, 2014;Fujimori et al, 2018;Kiskinis et al, 2014;Klim et al, 2019;Melamed et al, 2019;Sareen et al, 2013;Shi et al, 2018). We noted that bulk transcriptomic analysis may contribute to discrepancies in pathway discoveries, and thus sought to characterize these commonalities and distinctions using higher resolution, single-cell analysis.…”

Section: Single-cell Analysis Enables Attribution Of Early and Convermentioning

confidence: 99%

“…It is a neuron-specific RNA-binding protein whose expression starts embryonically and persists into adulthood (Okano and Darnell, 1997). Previous studies have noted disruption of ELAVL3 in ALS conditions (Colombrita et al, 2015;Klim et al, 2019), and because it regulates RNA processing, splicing, alternative poly-adenylation, and stabilizes translational control (Grassi et al, 2018), future studies investigating functional disruption of ELAVL3 may address whether it is an upstream pathway to MN degeneration shared among familial and sporadic ALS cases.…”

Section: Single-cell Analysis Of Als Ipsc-mns Highlights Putatively Cmentioning

confidence: 99%

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Single-cell RNA-seq analysis of human iPSC-derived motor neurons resolves early and predictive ALS signatures

Workman

Mathkar

et al. 2020

Preprint

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1 Summary Induced pluripotent stem cell (iPSC) derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can reflect disease phenotypes targetable by treatments. However, widely used differentiation protocols produce mixtures of progenitors, neurons, glia, and other cells at various developmental stages and rostrocaudal neural tube segments. Here we present a methodology using single-cell RNA sequencing analysis to distinguish cell type expression in C9orf72 ALS, sporadic ALS, control, and genome-edited cultures across multiple subjects, experiments, and commercial platforms. Combinations of HOX and developmental gene expression with global clustering classified rostrocaudal, progenitor, and mantle zone fates. This demonstrated that iPSC-differentiated cells recapitulate fetal hindbrain and spinal cord development and resolved early, reproducible, and motor neuron-specific signatures of familial and sporadic ALS. This includes downregulated ELAVL3 expression, which persists into disease endstages. Single-cell analysis thus yielded predictive ALS markers in other human and mouse models which were otherwise undiscovered through bulk omics assays.

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Section: Als Ipsc-mn Cultures Exhibit Transcriptional Changes Detectasupporting

confidence: 88%

Section: Single-cell Analysis Enables Attribution Of Early and Convermentioning

confidence: 99%

Section: Single-cell Analysis Enables Attribution Of Early and Convermentioning

confidence: 99%

Section: Single-cell Analysis Of Als Ipsc-mns Highlights Putatively Cmentioning

confidence: 99%

See 2 more Smart Citations

Single-cell RNA-seq analysis of human iPSC-derived motor neurons resolves early and predictive ALS signatures

Workman

Mathkar

et al. 2020

Preprint

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“…We recently reported that TDP-43 naturally de-mixes in the nucleus, and shuttles to the cytoplasm in response to multiple stresses (21). Loss of nuclear TDP-43 causes usage of cryptic splice (22)(23)(24) and polyadenylation sites (24), dysregulating many important neuronal genes such as HDAC6 (25) and stathmin-2 (22,24).…”

Section: Mislocalization and Aggregation Of The Heterogeneous Nuclearmentioning

confidence: 99%

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

Gasior

et al. 2020

Preprint

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One Sentence Summary:Acetylation of TDP-43 drives its phase separation into spherical annuli that form a liquid-insidea-liquid-inside-a-liquid. AbstractThe RNA binding protein TDP-43 naturally phase separates within cell nuclei and forms cytoplasmic aggregates in age-related neurodegenerative diseases. Here we show that acetylation-mediated inhibition of TDP-43 binding to RNA produces co-de-mixing of acetylated and unmodified TDP-43 into symmetrical, intranuclear spherical annuli whose shells and cores have liquid properties. Shells are anisotropic, like liquid crystals. Consistent with our modelling predictions that annulus formation is driven by components with strong self-interactions but weak interaction with TDP-43, the major components of annuli cores are identified to be HSP70 family proteins, whose chaperone activity is required to maintain liquidity of the core. Proteasome inhibition, mimicking reduction in proteasome activity during aging, induces TDP-43-containing annuli in neurons in rodents. Thus, we identify that TDP-43 phase separation is regulated by acetylation, proteolysis, and ATPase-dependent chaperone activity of HSP70.A seminal discovery in the last decade has been recognition that large biological molecules, especially RNA binding proteins, can undergo liquid-liquid phase separation (LLPS), resembling oil droplets in vinegar. Under certain physical conditions, proteins, nucleic acids, or a mixture of both in a complex solution can form two phases, a condensed de-mixed phase and more dilute aqueous phase (1). Inside the cell, proteins and/or nucleic acids de-mix into a condensed phase to form membraneless organelles which have been proposed to promote biological functions (2).One membraneless organelle is the nucleolus, first described in the early 1800's and now recognized to be composed of proteins that undergo LLPS (3-5). Discovery that P-granules are de-mixed compartments with liquid behaviour brought widespread recognition to LLPS and its ability to mediate subcellular compartmentalization in a biological context (6). Phase separation has been also proposed for heterochromatin and RNA bodies (1, 6, 7). LLPS potentially underlies the operational principle governing formation of important organelles and structures, such as centrosomes, nuclear pore complexes, and super enhancers (8-10).Few mechanisms to modulate intracellular LLPS have been identified. Disease-causing mutations of proteins such as FUS (11) and HNRNPA2B1 (12) alter their LLPS behaviors in vitro, but the physiological or pathological relevance of their intracellular LLPS has not been fully elucidated. Random, multivalent interactions among intrinsically disordered, low complexity domains (LCDs) of proteins are a major driving force for LLPS in vitro. Oligomerization of other domains is thought to be required for LLPS in vivo (13). The inherent randomness of multivalent interactions (14) favors a model of disordered alignment -a conventional liquid phase in which molecules randomly move. The evidence is compelling that multi...

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MATR3 pathogenic variants differentially impair its cryptic splicing repression function

Khan,

Chen,

Dias

et al. 2024

FEBS Letters

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Matrin‐3 (MATR3) is an RNA‐binding protein implicated in neurodegenerative and neurodevelopmental diseases. However, little is known regarding the role of MATR3 in cryptic splicing within the context of functional genes and how disease‐associated variants impact this function. We show that loss of MATR3 leads to cryptic exon inclusion in many transcripts. We reveal that ALS‐linked S85C pathogenic variant reduces MATR3 solubility but does not impair RNA binding. In parallel, we report a novel neurodevelopmental disease‐associated M548T variant, located in the RRM2 domain, which reduces protein solubility and impairs RNA binding and cryptic splicing repression functions of MATR3. Altogether, our research identifies cryptic events within functional genes and demonstrates how disease‐associated variants impact MATR3 cryptic splicing repression function.

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ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair

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Cited by 434 publications

References 64 publications

Single-cell RNA-seq analysis of human iPSC-derived motor neurons resolves early and predictive ALS signatures

Single-cell RNA-seq analysis of human iPSC-derived motor neurons resolves early and predictive ALS signatures

TDP-43 and HSP70 phase separate into anisotropic, intranuclear liquid spherical annuli

MATR3 pathogenic variants differentially impair its cryptic splicing repression function

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