Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD

Hayes, Lindsey R.; Kaláb, Petr

doi:10.1007/s13311-022-01260-5

Cited by 30 publications

(16 citation statements)

References 245 publications

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“…To our surprise we found TDP-43 overexpression and toxicity was associated with reduced, not enhanced, autophagy. This is consistent with experiments in other systems that show autophagy reduces TDP-43 toxicity [ 23 , 24 ] and TDP-43 aggregates inhibit autophagy [ 25 , 26 , 27 , 28 ]. Finally, we found that deletions of PBP1 and TIP41 , which reduced TDP-43 toxicity, also eliminated TDP-43′s inhibition of autophagy.…”

Section: Introductionsupporting

confidence: 91%

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

Park

Liebman

2022

Viruses

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When human TDP-43 is overexpressed in yeast it is toxic and forms cytoplasmic aggregates. The mechanism of this toxicity is unknown. Genetic screens for TDP-43 toxicity modifiers in the yeast system previously identified proteins, including PBP1, that enhance TDP-43 toxicity. The determination in yeast that deletion of PBP1 reduces TDP-43 toxicity while overexpression enhances toxicity, led to the discovery that its human homolog, ATXN2, is associated with ALS risk. Thus, the yeast system has relevance to human disease. We now show that deletion of a new yeast gene, tip41Δ, likewise suppresses TDP-43 toxicity. We also found that TDP-43 overexpression and toxicity is associated with reduced autophagy. This is consistent with findings in other systems that increasing autophagy reduces TDP-43 toxicity and is in contrast to a report of enhanced autophagy when TDP-43 was overexpressed in yeast. Interestingly, we found that deletions of PBP1 and TIP41, which reduced TDP-43 toxicity, eliminated TDP-43′s inhibition of autophagy. This suggests that toxicity of TDP-43 expressed in yeast is in part due to its inhibition of autophagy and that deletions of PBP1 and TIP41 may reduce TDP-43 toxicity by preventing TDP-43 from inhibiting autophagy.

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Section: Introductionsupporting

confidence: 91%

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

Park

Liebman

2022

Viruses

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“…However, TDP-43 plays a key role in many cellular processes 15 and thus may not be an ideal target for silencing. Instead, attention has turned to the identification of modifier(s) whose targeting can attenuate the apparent toxic effects induced by aberrant TDP-43 but without affecting its underlying levels [20][21][22][23][24] . Ataxin-2 has emerged as one such candidate.…”

Section: Discussionmentioning

confidence: 99%

“…However, despite its central role in neurodegeneration, numerous lines of evidence suggest that TDP-43 may not be an appropriate target for therapeutic silencing, as it plays a key role in numerous cellular processes 15 and its depletion from cells can induce various side effects [16][17][18][19] . Instead, attempts have been undertaken to identify modifier(s) whose targeting can attenuate the apparent toxic effects induced by aberrant TDP-43 without affecting its levels [20][21][22][23][24] . One such modifier is ataxin-2 20,25,26 , a polyglutamine-containing RNA binding protein thought to be involved in regulating mRNA translation 27 that, when mutated to carry an intermediate-length polyglutamine expansion, also emerges as a risk factor for ALS 20,[28][29][30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins

Moore

Powell

et al. 2023

Preprint

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The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7-11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7-11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.

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“…A link emerged after a report from our laboratory showed that HuR regulates the expression of TDP‐43 and FUS, two RNA‐binding proteins directly tied to ALS (Baloh, 2012; Lu et al, 2014). TDP‐43 pathology, including intracellular aggregation and cytoplasmic mislocalization, has been identified in motor neurons and glia in more than 95% of ALS patients (Hayes & Kalab, 2022). To mediate this regulation, HuR binds to a region in the TDP‐43 3’ UTR, near where TDP‐43 binds to autoregulate its own expression (Buratti & Baralle, 2012; Lu et al, 2014).…”

Section: Cns Disorders Where Are‐mediated Rna Regulation Has Been Inv...mentioning

confidence: 99%

RNA regulation of inflammatory responses in glia and its potential as a therapeutic target in central nervous system disorders

Guha

Husain

et al. 2022

Glia

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A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1β, TNF-α, iNOS, and IL-6.Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease.Posttranscriptional pathways of mRNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine-and uridine-rich element (ARE) which is present in the 3 0 untranslated region (UTR) of the mRNAs encoding these inflammatory mediators. (ARE)-binding proteins (AUBPs) such as Human antigen R (HuR), Tristetraprolin (TTP) and KH-type splicing regulatory protein (KSRP) are key nodes for directing these posttranscriptional pathways and either promote (HuR) or suppress (TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.

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Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD

Cited by 30 publications

References 245 publications

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

TDP-43 Toxicity in Yeast Is Associated with a Reduction in Autophagy, and Deletions of TIP41 and PBP1 Counteract These Effects

Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins

RNA regulation of inflammatory responses in glia and its potential as a therapeutic target in central nervous system disorders

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