Small Molecule Targeting TDP-43’s RNA Recognition Motifs Reduces Locomotor Defects in a <i>Drosophila</i> Model of Amyotrophic Lateral Sclerosis (ALS)

François‐Moutal, Liberty; Felemban, Razaz; Scott, David D.; Sayegh, Melissa; Miranda, Victor G.; Perez‐Miller, Samantha; Khanna, Rajesh; Gokhale, Vijay; Zarnescu, Daniela C.; Khanna, May

doi:10.1021/acschembio.9b00481

Cited by 50 publications

(50 citation statements)

References 42 publications

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“…Supporting a role for RNA as a factor inducing toxicity is the recent identification of small molecules that can bind TDP-43 and displace G quadruplex like structures but not canonical UG repeats. Notably, one of these structures identified using in silico design also mitigates TDP-43 dependent toxicity in vivo, in a Drosophila model of ALS (Francois-Moutal et al, 2019). Although it remains to be determined whether this small molecule works in vivo by actually binding TDP-43 and displacing mRNA targets, the findings provide proof of principle that targeting the RRM domain of TDP-43 may provide strategies for mitigating toxicity at least in the context of TDP-43 overexpression.…”

Section: Rna As a Toxic Factormentioning

confidence: 89%

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Loganathan

Lehmkuhl

Eck

et al. 2020

Front. Mol. Biosci.

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TAR DNA binding protein (TDP-43) is a nucleic acid binding protein associated with insoluble cytoplasmic aggregates in several neurodegenerative disorders, including 97% of the ALS cases. In healthy individuals, TDP-43 is primarily localized to the nucleus; it can shuttle between the nucleus and the cytoplasm, and is involved in several aspects of RNA processing including transcription, splicing, RNA stability, transport, localization, stress granule (SG) formation, and translation. Upon stress, TDP-43 aggregates in the cytoplasm and associates with several types of RNA and protein assemblies, resulting in nuclear depletion of TDP-43. Under conditions of prolonged stress, cytoplasmic TDP-43 undergoes liquid-liquid phase separation (LLPS) and becomes less mobile. Evidence exists to support a scenario in which insoluble TDP-43 complexes sequester RNA and/or proteins causing disturbances in both ribostasis and proteostasis, which in turn contribute to neurodegeneration. However, the relationship between RNA binding and TDP-43 toxicity remains unclear. Recent studies provide conflicting views on the role of RNA in TDP-43 toxicity, with some finding RNA as a toxic factor whereby RNA binding contributes to TDP-43 toxicity, while others find RNA to be a protective factor that inhibits TDP-43 aggregation. Here we review and discuss these recent reports, which ultimately highlight the importance of understanding the heterogeneity of TDP-43 assemblies and collectively point to solubilizing TDP-43 as a potential therapeutic strategy.

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Section: Rna As a Toxic Factormentioning

confidence: 89%

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Loganathan

Lehmkuhl

Eck

et al. 2020

Front. Mol. Biosci.

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“…414-Residue TDP-43 contains two folded RRM domains (Fig. 1 A), which are not only essential for recognizing UG-rich sequences near RNA splice sites 11 , but also extensively demonstrated to participate in disease-causing aggregation/fibrillation in additional to its C-terminal prion-like domain 11 – 19 . Remarkably, small molecules targeting the RRM domains of TDP-43 have been recently identified to reduce locomotor defects in drosophila model of ALS 19 .…”

Section: Introductionmentioning

confidence: 99%

“…1 A), which are not only essential for recognizing UG-rich sequences near RNA splice sites 11 , but also extensively demonstrated to participate in disease-causing aggregation/fibrillation in additional to its C-terminal prion-like domain 11 – 19 . Remarkably, small molecules targeting the RRM domains of TDP-43 have been recently identified to reduce locomotor defects in drosophila model of ALS 19 . We also found that ATP, the universal energy currency, specifically binds the RRM domains of FUS and TDP-43 to inhibit their amyloid fibrillation 20 – 22 .…”

Section: Introductionmentioning

confidence: 99%

Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Dang

Song

2021

Sci Rep

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TDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

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“…1A), which are not only essential for recognizing UG-rich sequences near RNA splice sites (11), but also extensively demonstrated to participate in disease-causing aggregation/fibrillation in additional to its Cterminal prion-like domain (11)(12)(13)(14)(15)(16)(17)(18)(19). Remarkably, small molecules targeting the RRM domains of TDP-43 have been recently identified to reduce locomotor defects in drosophila model of ALS (19). We also found that ATP, the universal energy currency, specifically binds the RRM domains of FUS and TDP-43 to inhibit their amyloid fibrillation (20)(21)(22).…”

mentioning

confidence: 99%

“…Briefly, the FUS RRM domain undergoes fibrillation not only due to its relatively low stability with melting temperature (Tm) of 55 ºC, lower than that of the human gS-crystallin with Tm of 71 ºC (24), but also resulting from its high conformational dynamics, that allow the dynamic opening of the structure to expose its central hydrophobic regions for aggregation/fibrillation (23). Consequently, although ATP induces no enhancement of the thermal stability of the FUS RRM domain, it is sufficient to kinetically inhibit the amyloid fibrillation through weak but specific binding with a Kd of 3.77 mM to a pocket within the conserved nucleic-acid-binding surfaces, which thus leads to blocking the dynamic opening of the structure (19).…”

mentioning

confidence: 99%

Stabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Dang

Song

2020

Preprint

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TDP-43 and hnRNPA1 contain tandemly-tethered RRM domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including ALS, FTD, AD and MSP. Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: 1) very unexpectedly, upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. 2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity higher to the tethered than isolated forms. 3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1-RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

show abstract

Small Molecule Targeting TDP-43’s RNA Recognition Motifs Reduces Locomotor Defects in a Drosophila Model of Amyotrophic Lateral Sclerosis (ALS)

Cited by 50 publications

References 42 publications

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

To Be or Not To Be…Toxic—Is RNA Association With TDP-43 Complexes Deleterious or Protective in Neurodegeneration?

Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Stabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

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