Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser

Kan, Hung‐Wei; Chiang, Hou‐Yu; Wan, Lin; Yu, I-Shing; Lin, S.-W.; Hsieh, Sung‐Tsang

doi:10.1111/nan.12477

Cited by 12 publications

(20 citation statements)

References 54 publications

(76 reference statements)

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“…To demonstrate amyloids, we stained skin sections using the conventional Congo red (pH = 11.0) protocol . This was in contrast to the Congo red (pH = 8.0) protocol, which did not reveal amyloids, but sweat glands for SGII(PGP9.5) quantification .…”

Section: Methodsmentioning

confidence: 99%

“…However, it is not clear whether the skin innervation reflects the progression of FAP, a critical indicator and prognostic factor in FAP treatment . Because amyloid is a pathognomonic sign of FAP, a further critical issue is to examine amyloid deposition in the skin biopsies quantitatively and to analyze its relationships to skin nerve degeneration during the course of FAP stages.…”

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confidence: 99%

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Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Chao

Hsueh

Kan

et al. 2019

Annals of Neurology

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Objective: Small-fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease-progression biomarkers and their relationship with skin amyloid deposits. Methods: Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 (SGII[PGP9.5]) and peptidergic vasoactive intestinal peptide (SGII[VIP]), and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0-4) and compared to neurophysiological and psychophysical tests. Results: There were 70 TTR-mutant subjects (22 carriers and 48 patients), and 66 cases were TTR-A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariate mixed-effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers. Interpretation: Biomarkers of sensory and sudomotor innervation exhibited a stage-dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Chao

Hsueh

Kan

et al. 2019

Annals of Neurology

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“…After stimulation, cells were washed by Dulbecco's Phosphate-Buffered Saline (DPBS) and detached by using Accutase Cell Detachment Solution (BD Biosciences). Cells for TEM were processed as described previously (37). In brief, cells were pelleted, fixed in 5% glutaraldehyde, post-fixed with 2% osmic acid, dehydrated, and embedded in Epon 812 resin (Polysciences).…”

Section: Methodsmentioning

confidence: 99%

NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages

Huang

Liu

et al. 2018

Front. Immunol.

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LC3-associated phagocytosis (LAP) is an emerging non-canonical autophagy process that bridges signaling from pattern-recognition receptors (PRRs) to autophagic machinery. LAP formation results in incorporation of lipidated LC3 into phagosomal membrane (termed LAPosome). Increasing evidence reveals that LAP functions as an innate defense mechanism against fungal pathogens. However, the molecular mechanism involved and the consequence of LAP in regulating anti-fungal immune response remain largely unexplored. Here we show that Histoplasma capsulatum is taken into LAPosome upon phagocytosis by macrophages. Interaction of H. capsulatum with Dectin-1 activates Syk and triggers subsequent NADPH oxidase-mediated reactive oxygen species (ROS) response that is involved in LAP induction. Inhibiting LAP induction by silencing LC3α/β or treatment with ROS inhibitor impairs the activation of MAPKs-AP-1 pathway, thereby reduces macrophage proinflammatory cytokine response to H. capsulatum. Additionally, we unravel the importance of NLRX1 in fungus-induced LAP. NLRX1 facilitates LAP by interacting with TUFM which associates with autophagic proteins ATG5-ATG12 for LAPosome formation. Macrophages from Nlrx1−/− mice or TUFM-silenced cells exhibit reduced LAP induction and LAP-mediated MAPKs-AP-1 activation for cytokine response to H. capsulatum. Furthermore, inhibiting ROS production in Nlrx1−/− macrophages almost completely abolishes H. capsulatum-induced LC3 conversion, indicating that both Dectin-1/Syk/ROS-dependent pathway and NLRX1-TUFM complex-dependent pathway collaboratively contribute to LAP induction. Our findings reveal new pathways underlying LAP induction by H. capsulatum for macrophage cytokine response.

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“…Attempts to model ATTR amyloidosis in mice began more than 3 decades ago by random genomic insertion of wild-type or mutant hTTR. However, efforts to produce an ideal mouse model for ATTR amyloidosis have not been as successful as scientists would desire (Buxbaum et al, 2003; Buxbaum, 2009; Kan et al, 2018; Li et al, 2018). To gain insights into the pathogenesis of ATTR amyloidosis, transgenic ATTR V30M mice were created with the mouse metallothionein promoter (Shimada et al, 1989).…”

Section: Rodent Attr Modelsmentioning

confidence: 99%

Contributions of Animal Models to the Mechanisms and Therapies of Transthyretin Amyloidosis

Ibrahim

Liu

Yeh³

et al. 2019

Front. Physiol.

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Transthyretin amyloidosis (ATTR amyloidosis) is a fatal systemic disease caused by amyloid deposits of misfolded transthyretin, leading to familial amyloid polyneuropathy and/or cardiomyopathy, or a rare oculoleptomeningeal amyloidosis. A good model system that mimic the disease phenotype is crucial for the development of drugs and treatments for this devastating degenerative disorder. The present models using fruit flies, worms, rodents, non-human primates and induced pluripotent stem cells have helped researchers understand important disease-related mechanisms and test potential therapeutic options. However, the challenge of creating an ideal model still looms, for these models did not recapitulates all symptoms, particularly neurological presentation, of ATTR amyloidosis. Recently, knock-in techniques was used to generate two humanized ATTR mouse models, leading to amyloid deposition in the nerves and neuropathic manifestation in these models. This review gives a recent update on the milestone, progress, and challenges in developing different models for ATTR amyloidosis research.

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Sensory nerve degeneration in a mouse model mimicking early manifestations of familial amyloid polyneuropathy due to transthyretin Ala97Ser

Abstract: These results demonstrate that the hTTR mouse model develops sensory nerve pathology and corresponding physiology mimicking A97S-FAP and provides a platform to develop new therapies for the early stage of A97S-FAP.

Cited by 12 publications

References 54 publications

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

NLRX1 Facilitates Histoplasma capsulatum-Induced LC3-Associated Phagocytosis for Cytokine Production in Macrophages

Contributions of Animal Models to the Mechanisms and Therapies of Transthyretin Amyloidosis

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