Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice

Takeuchi, Toshihide; Maeta, Kazuhiro; Ding, Xiangdong; Oe, Yukako; Inoue, Mana; Nagano, Seiichi; Fujihara, Tsuyoshi; Matsuda, Seiji; Ishigaki, Shinsuke; Sahashi, Kentaro; Minakawa, Eiko N.; Mochizuki, Hideki; Neya, Masahiro; Sobue, Gen; Nagai, Yoshitaka

doi:10.1016/j.omtn.2023.01.006

Cited by 10 publications

(3 citation statements)

References 45 publications

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“…Although it remains unclear as to how TDP-43 aggregation causes neurodegeneration in patients with ALS/FTD, suppressing TDP-43 aggregation will potentially rescue neurons from TDP-43 toxicity. Indeed, we recently showed that a transient reduction in TDP-43 levels by antisense oligonucleotides leads to the suppression of cytoplasmic TDP-43 aggregation, and long-lasting improvement in behavioral abnormalities in ALS/FTD mice [ 36 ]. In the present study, we showed that knockdown of DCTN1 and other microtubule-dependent motor proteins facilitates TDP-43 aggregation and exacerbates neurodegeneration in vivo (Figs.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Ueda,

Takeuchi,

Fujikake

et al. 2024

acta neuropathol commun

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The abnormal aggregation of TDP-43 into cytoplasmic inclusions in affected neurons is a major pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 is aberrantly accumulated in the neurons of most patients with sporadic ALS/FTD and other TDP-43 proteinopathies, how TDP-43 forms cytoplasmic aggregates remains unknown. In this study, we show that a deficiency in DCTN1, a subunit of the microtubule-associated motor protein complex dynactin, perturbs the dynamics of stress granules and drives the formation of TDP-43 cytoplasmic aggregation in cultured cells, leading to the exacerbation of TDP-43 pathology and neurodegeneration in vivo. We demonstrated using a Drosophila model of ALS/FTD that genetic knockdown of DCTN1 accelerates the formation of ubiquitin-positive cytoplasmic inclusions of TDP-43. Knockdown of components of other microtubule-associated motor protein complexes, including dynein and kinesin, also increased the formation of TDP-43 inclusions, indicating that intracellular transport along microtubules plays a key role in TDP-43 pathology. Notably, DCTN1 knockdown delayed the disassembly of stress granules in stressed cells, leading to an increase in the formation of pathological cytoplasmic inclusions of TDP-43. Our results indicate that a deficiency in DCTN1, as well as disruption of intracellular transport along microtubules, is a modifier that drives the formation of TDP-43 pathology through the dysregulation of stress granule dynamics.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Ueda,

Takeuchi,

Fujikake

et al. 2024

acta neuropathol commun

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“…21,22,64 ASOs are also being pursued against FUS, ataxin 2, and TDP-43 as potential therapeutics for ALS/FTD with promising results in model systems and progression to clinical trials. [65][66][67] Nonetheless, this strategy runs the risk of promoting loss of function toxicity due to knockdown of these targets, which may be particularly problematic for TDP-43. 68 By contrast, our short RNAs would restore RBPs to native structure and function thereby eliminating toxicity due to gain and loss of function, which could yield more powerful therapeutic effects.…”

Section: Discussionmentioning

confidence: 99%

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

Guo,

Mann,

Mauna

et al. 2023

Preprint

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RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.

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“…As an alternative, efforts to resolve the aggregates into which Nups are sequestered could liberate Nups, restoring their functionality [ 310–313 ]. Disaggregation can be achieved directly by reducing levels of aggregation-prone molecules, such as TDP-43 [ 314 , 315 ], FUS [ 200 ], and SOD1 [ 316 , 317 ]. Aggregation can also be mitigated indirectly by enhancing the activity of endogenous chaperones, such as NTRs [ 35 , 43 , 48 , 310 , 318–320 ].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Nuclear pore dysfunction and disease: a complex opportunity

Fare,

Rothstein

2024

Nucleus

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The separation of genetic material from bulk cytoplasm has enabled the evolution of increasingly complex organisms, allowing for the development of sophisticated forms of life. However, this complexity has created new categories of dysfunction, including those related to the movement of material between cellular compartments. In eukaryotic cells, nucleocytoplasmic trafficking is a fundamental biological process, and cumulative disruptions to nuclear integrity and nucleocytoplasmic transport are detrimental to cell survival. This is particularly true in post-mitotic neurons, where nuclear pore injury and errors to nucleocytoplasmic trafficking are strongly associated with neurodegenerative disease. In this review, we summarize the current understanding of nuclear pore biology in physiological and pathological contexts and discuss potential therapeutic approaches for addressing nuclear pore injury and dysfunctional nucleocytoplasmic transport.

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Sustained therapeutic benefits by transient reduction of TDP-43 using ENA-modified antisense oligonucleotides in ALS/FTD mice

Cited by 10 publications

References 45 publications

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Dysregulation of stress granule dynamics by DCTN1 deficiency exacerbates TDP-43 pathology in Drosophila models of ALS/FTD

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

Nuclear pore dysfunction and disease: a complex opportunity

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