Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Camdessanché, J.-P.; Belzil, Véronique V.; Jousserand, Guillemette; Rouleau, Guy A.; Créac’h, C.; Convers, Philippe; Antoine, J. C.

doi:10.1186/1750-1172-6-4

Cited by 20 publications

(16 citation statements)

References 24 publications

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“…Compared to previously reported wild-type TDP-43 models, codon-optimized TDP-43 flies exhibit robust eye, wing, and bristle phenotypes, mirroring disease-specific characteristics of TDP-43 (summarized in Table 1). Our findings are in line with previous studies that associated pathogenic mutations in TDP-43 to severely damaged sensory neurons, affecting both the central and peripheral nervous systems in patients (Camdessanche et al 2011). The robust phenotypes observed in our study are indicative of cellular dysfunction and death, and are probable markers for neurodegenerative models.…”

Section: Discussionsupporting

confidence: 93%

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Yusuff

Chatterjee

Chang

et al. 2019

Preprint

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59Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration 60 associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The 61 exact mechanism by which TDP-43 exerts toxicity in the brains of affected patients remains unclear. In 62 a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of 63 insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary 64 GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue 65 specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized 66 transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, 67 exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and 68 cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in 69 the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are 70 characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to 71 form toxic protein aggregates via a gain-of-function mechanism, and such toxic overload leads to 72 activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 73model is an excellent resource that could be used in genetic screens to identify and better understand the 74 exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets. 75 76 77 78 79 80 4 103 5 (Johnson et al.

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Section: Discussionsupporting

confidence: 93%

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Yusuff

Chatterjee

Chang

et al. 2019

Preprint

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“…The frequency of gene variants in cases with extra-motor involvement is significantly higher compared to the pure ALS phenotype, and has been associated with poorer survival (McCluskey et al, 2014). Prominent sensory involvement had been described in rare mutated cases, with SOD1 and TARDBP genes being reported most frequently (Camdessanche et al, 2011).…”

Section: The Pns As a Converging Point In Alsmentioning

confidence: 99%

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

et al. 2019

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Although amyotrophic lateral sclerosis (ALS) has been considered as a disorder of the motor neuron (MN) cell body, recent evidences show the non-cell-autonomous pathogenic nature of the disease. Axonal degeneration, loss of peripheral axons and destruction of nerve terminals are early events in the disease pathogenic cascade, anticipating MN degeneration, and the onset of clinical symptoms. Therefore, although ALS and peripheral axonal neuropathies should be differentiated in clinical practice, they also share damage to common molecular pathways, including axonal transport, RNA metabolism and proteostasis. Thus, an extensive evaluation of the molecular events occurring in the peripheral nervous system (PNS) could be fundamental to understand the pathogenic mechanisms of ALS, favoring the discovery of potential disease biomarkers, and new therapeutic targets.

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“… 9 In further support of the pathogenicity of the TDP43 inclusions in the DRG is the recent report of a patient with an asymmetric patchy and progressive sensory and motor neuronopathy in whom a p.Arg382Pro missense mutation in TARDBP was discovered. 10 This mutation is not present in the Exac database and has previously been described in patients with ALS. 11 An additional distinctive feature seen in this patient and reported in the literature 8 is the presence of widespread glial TDP43 pathology.…”

Section: Discussionmentioning

confidence: 93%

TDP43 pathology in the brain, spinal cord, and dorsal root ganglia of a patient with FOSMN

Rossor¹,

Jaunmuktane²,

Hoti³

2019

Neurology

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Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation

Cited by 20 publications

References 24 publications

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

The Peripheral Nervous System in Amyotrophic Lateral Sclerosis: Opportunities for Translational Research

TDP43 pathology in the brain, spinal cord, and dorsal root ganglia of a patient with FOSMN

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