Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs

Keuss, Matthew J.; Harly, Peter; Ryadnov, Eugeni; Jackson, Rachel E.; Zanovello, Matteo; Wilkins, Oscar G.; Barattucci, Simone; Mehta, Puja R.; Oliveira, Marcio G.; Parkes, Joanna E.; Sinha, Aparna; Correa-Sánchez, Andrés F.; Oliver, Peter L.; Fisher, Elizabeth M.C.; Schiavo, Giampietro; Shah, Mala; Burrone, Juan; Fratta, Pietro

doi:10.1101/2024.06.20.599684

Cited by 3 publications

References 33 publications

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Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

Eisen,

Vucic,

Kiernan

2024

Muscle and Nerve

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Several decades have passed since the anterograde corticomotoneuronal hypothesis for amyotrophic lateral sclerosis (ALS) was proposed. The intervening years have witnessed its emergent support based on anatomical, pathological, physiological, neuroimaging, and molecular biological studies. The evolution of an extensive corticomotoneuronal system appears restricted to the human species, with ALS representing a uniquely human disease. While some, very select non‐human primates have limited corticomotoneuronal projections, these tend to be absent in all other animals. From a general perspective, the early clinical features of ALS may be considered to reflect failure of the corticomotoneuronal system. The characteristic loss of skilled motor dexterity involving the limbs, and speech impairment through progressive bulbar dysfunction specifically involve those motor units having the strongest corticomotoneuronal projections. A similar explanation likely underlies the unique “split phenotypes” that have now been well characterized in ALS. Large Betz cells and other pyramidal corticomotoneuronal projecting neurons, with their extensive dendritic arborization, are particularly vulnerable to the elements of the ALS exposome such as aging, environmental stress and lifestyle changes. Progressive failure of the proteosome impairs nucleocytoplasmic shuffling and induces toxic but soluble TDP‐43 to aggregate in corticomotoneurons. Betz cell failure is further accentuated through dysfunction of its profuse dendritic arborizations. Clarification of system specific genomes and neural networks will likely promote the initiation of precision medicine approaches directed to support the key structure that underlies the neurological manifestations of ALS, the corticomotoneuronal system.

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Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

Eisen,

Vucic,

Kiernan

2024

Muscle and Nerve

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A phase Ib/IIa randomized trial of Enoxacin in patients with ALS

Magen,

Kaneb,

Masnata

et al. 2024

Preprint

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The RNAse III DICER is essential for miRNA biogenesis. DICER activity is downregulated in sporadic and genetic forms of ALS. Accordingly, hundreds of miRNAs are broadly downregulated, and their mRNA targets are de-repressed. Enoxacin is a fluoroquinolone, which increases DICER activity and miRNA biogenesis. In an investigator-initiated, first-in- patient phase Ib/IIa study we tested Enoxacin safety and tolerability in patients with ALS and explored pharmacodynamic biomarkers for Enoxacin target engagement. Six patients with sporadic ALS were dosed with oral Enoxacin twice daily for 30 days. Patients did not experience any serious adverse events and completed the dosing period. Molecular analysis of cell-free miRNA in plasma and CSF revealed a global increase in plasma and CSF miRNA levels in all post-treatment time points, compared to baseline. Therefore, our study demonstrates that Enoxacin is tolerable and provides important evidence for in-patient target engagement. These results encourage testing Enoxacin efficacy in larger trials.

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ALS-associated RNA binding proteins converge onUNC13Atranscription through regulation of REST

Watanabe,

Suzuki,

Nakagawa

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Although multiple pathophysiological mechanisms have been identified, a unified molecular basis for ALS has remained elusive. The ALS-associated RNA binding protein (RBP) TDP-43 has previously been shown to stabilize UNC13A mRNA by preventing cryptic exon inclusion. We here show that three ALS-associated RBPs, MATR3, FUS, and hnRNPA1 regulate UNC13A expression by targeting the silencing transcription factor REST. These three RBPs bind to and downregulate REST mRNA and thereby promote UNC13A transcription. REST overexpression was detected not only in response to the loss of each of these three RBPs in cultured cells but also in motor neurons of individuals with familial or sporadic ALS. The functional convergence of four RBPs on the regulation of UNC13A, a gene essential for synaptic transmission, highlights a pivotal contribution of these proteins to maitainance of synaptic integrity. Our findings thus provide key insight into ALS pathogenesis and a basis for the development of new therapeutic agents.

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Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs

Cited by 3 publications

References 33 publications

Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

Amyotrophic lateral sclerosis represents corticomotoneuronal system failure

A phase Ib/IIa randomized trial of Enoxacin in patients with ALS

ALS-associated RNA binding proteins converge onUNC13Atranscription through regulation of REST

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