Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

Dyer, Marcus S; Reale, Laura A; Lewis, Katherine E; Walker, Adam K.; Dickson, Tracey C.; Woodhouse, Adele; Blizzard, CL

doi:10.1111/jnc.15214

Cited by 44 publications

(59 citation statements)

References 71 publications

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“…The most likely disease profile of an ALS patient is no known genetic mutation, focal motor cortex hyperexcitability which has the propensity to cause widespread network dysfunction and TDP-43 protein which is excluded from the motor neuron nucleus [10,19]. How these critical disease profiles interact is only starting to be comprehended [13,20] and how these changes result ultimately in neuronal demise remains an important research question. Therefore, we endeavoured to interrogate whether TDP-43 mislocalization contributes to the generation of upper motor neuron dysfunction through altering neuronal circuitry.…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous Thy1-YFP transgenic mice (B6.Cg-Tg(Thy1-YFP)HJrs/J/ Stock No: 003782) [28,29] were crossed with previously described Camk2α-tTa (B6;CBA-Tg(Camk2a-tTA)1Mmay/Stock No: 003010). Mice heterozygous for Thy1-YFP and Camk2α-tTa were bred with tetO-TDP-43∆NLS (B6;C3-Tg(tetO-TARDBP*)4Vle/J/Stock No: 014650) and tetO-TDP-43 WT mice (B6;C3-Tg(tetO-TARDBP)12Vle/J/Stock No: 016841) [20,27]. These strains have inducible expression of TDP-43 with the removal of doxycycline from their diet.…”

Section: Mouse Cohortmentioning

confidence: 99%

“…This implies that the mislocalization of TDP-43 is critical to the progression of ALS irrespective of mutation status of the person living with ALS. Recent discoveries now link wild-type TDP-43 pathology with hyperexcitability in the motor cortex [20,21]. These studies have provided the bridge between the most frequent pathology of ALS and a conserved pathophysiological presentation of the disease, highlighting the potential importance of TDP-43 mislocalization.…”

Section: Introductionmentioning

confidence: 99%

“…The total levels of TDP-43 in the TDP-43 ∆NLS brain are higher than that in TDP-43 WT , presumably due to impaired regulation of the TDP-43 in the cytoplasm [27]. We analysed these mice at post-natal day 60, with 30 days of induced transgene expression, a timepoint which we have previously shown is before extensive neuron loss [20]. To quantify the density of spines in the primary motor cortex the TDP-43 WT and TDP-43 ∆NLS mice were crossed with Thy1-YFPH mice, which express fluorescent protein in layer V neurons in the cortex [28].…”

Section: Introductionmentioning

confidence: 99%

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Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons

2021

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Amyotrophic lateral sclerosis (ALS) is defined by the destruction of upper- and lower motor neurons. Post-mortem, nearly all ALS cases are positive for cytoplasmic aggregates containing the DNA/RNA binding protein TDP-43. Recent studies indicate that this pathogenic mislocalization of TDP-43 may participate in generating hyperexcitability of the upper motor neurons, the earliest detectable change in ALS patients, yet the mechanisms driving this remain unclear. We investigated how mislocalisation of TDP-43 could initiate network dysfunction in ALS. We employed a tetracycline inducible system to express either human wildtype TDP-43 (TDP-43WT) or human TDP-43 that cannot enter the nucleus (TDP-43ΔNLS) in excitatory neurons (Camk2α promoter), crossed Thy1-YFPH mice to visualize dendritic spines, the major site of excitatory synapses. In comparison to both TDP-43WT and controls, TDP-43ΔNLS drove a robust loss in spine density in all the dendrite regions of the upper motor neurons, most affecting thin spines. This indicates that TDP-43 is involved in the generation of network dysfunction in ALS likely through impacting the formation or durability of excitatory synapses. These findings are relevant to the vast majority of ALS cases, and provides further evidence that upper motor neurons may need to be protected from TDP-43 mediated synaptic excitatory changes early in disease.

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Section: Discussionmentioning

confidence: 99%

Section: Mouse Cohortmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons

2021

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“…Muscle weakness and rigidity, CFS, exhaustion, and sleep disorders (e.g., insomnia, REM sleep behavior disorder) are the most common chronic symptoms observed in patients post-COVID-19recovery [14]. There has not been sufficient time to study and understand the long-term impacts and implications of COVID-19 in depth since the beginning of the pandemic; however, recent studies have identified substantial and long-term adverse health effects.…”

Section: Introductionmentioning

confidence: 99%

Health Complications in Patients Recovering from COVID-19: A Narrative Review of Post-COVID Syndrome

Pai

Park

Chen

et al. 2021

JAMMR

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Introduction: Due to the unprecedented health and economic complications resulting from COVID-19, the coronavirus pandemic is currently a leading global health concern. COVID-19 poses significant health risks, life-threatening clinical conditions, and even mortality in affected individuals. Several associated complications have also arisen as a result of COVID-19, including mass hospitalization, the need for invasive ventilation and intensive care unit (ICU) support, delayed recovery from infection, and post-recovery health issues. Furthermore, the pandemic itself has created enormous panic, which in turn affects the mental health of COVID-19 patients, individuals who have recovered from the disease, and the general population. Just over a year has now passed since the beginning of the global COVID-19 pandemic and in this time, over 110 million individuals have been infected worldwide. Post-infection recovery times and long-term complications are now becoming more apparent. Especially physical and mental health complications arising from post-COVID-19-infection, which prevent a return to a healthy lifestyle and everyday routine remain a critical issue. Objective: The primary objective of this narrative review is to address this clinically relevant issue and overview the health complications commonly observed in individuals who have recovered from COVID-19. Methods: An investigation was performed on online databases for relevant articles from 2020 until January 2021. Key index words used in search were post-covid, myalgia, fatigue, pain. Results: Fatigue, myalgia (i.e., muscle pain), sleep disruptions, and mental health issues (e.g., anxiety and depression) are among the most reported post-recovery symptoms in patients recovering from the disease. The etiology and potential management of these health complications are discussed, considering recently published findings from COVID-19 patients as well as previous studies focusing on complications arising from other related pandemics. Conclusion: Patients who have recovered from COVID-19 should be evaluated for signs of fatigue, muscle pain, mental health difficulties, and sleeping difficulties regardless of disease severity. Based on this review of the literature, complete clinical and psychiatric evaluation, and the use of validated indicators of the severity of COVID-19 disease, symptoms are recommended to develop efficient health management approaches that meet patients' needs.

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Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

Clark,

Lewis

et al. 2023

Ann Clin Transl Neurol

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ObjectiveNeuropeptide Y (NPY) is a 36 amino acid peptide widely considered to provide neuroprotection in a range of neurodegenerative diseases. In the fatal motor neuron disease amyotrophic lateral sclerosis (ALS), recent evidence supports a link between NPY and ALS disease processes. The goal of this study was to determine the therapeutic potential and role of NPY in ALS, harnessing the brain‐targeted intranasal delivery of the peptide, previously utilised to correct motor and cognitive phenotypes in other neurological conditions.MethodsTo confirm the association with clinical disease characteristics, NPY expression was quantified in post‐mortem motor cortex tissue of ALS patients and age‐matched controls. The effect of NPY on ALS cortical pathophysiology was investigated using slice electrophysiology and multi‐electrode array recordings of SOD1G93A cortical cultures in vitro. The impact of NPY on ALS disease trajectory was investigated by treating SOD1G93A mice intranasally with NPY and selective NPY receptor agonists and antagonists from pre‐symptomatic and symptomatic phases of disease.ResultsIn the human post‐mortem ALS motor cortex, we observe a significant increase in NPY expression, which is not present in the somatosensory cortex. In vitro, we demonstrate that NPY can ameliorate ALS hyperexcitability, while brain‐targeted nasal delivery of NPY and a selective NPY Y1 receptor antagonist modified survival and motor deficits specifically within the symptomatic phase of the disease in the ALS SOD1G93A mouse.InterpretationTaken together, these findings highlight the capacity for non‐invasive brain‐targeted interventions in ALS and support antagonism of NPY Y1Rs as a novel strategy to improve ALS motor function.

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Mislocalisation of TDP‐43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex

Abstract: Title: Amyotrophic lateral sclerosis associated mislocalisation of TDP-43 to the cytoplasm causes cortical hyperexcitability and reduced excitatory neurotransmission in the motor cortex.

Cited by 44 publications

References 71 publications

Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons

Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons

Health Complications in Patients Recovering from COVID-19: A Narrative Review of Post-COVID Syndrome

Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

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