Transthyretin regulates hippocampal 14‐3‐3ζ protein levels

Vieira, Marta; Saraiva, Maria João

doi:10.1016/j.febslet.2013.03.011

Cited by 16 publications

(11 citation statements)

References 48 publications

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“…Hippocampus of young TTR null mice presented lower levels of 14-3-3ζ protein, but no changes in gene expression. Lysosomal degradation of 14-3-3ζ in the absence of TTR was the mechanism proposed for the reduced 14-3-3ζ levels (89). Hippocampal slice cultures of TTR null mice did not present increased cellular death when compared wild-type animals (90), suggesting that the decreased levels of 14-3-3ζ observed in these animals are not associated with increased cellular death.…”

Section: Ttr In the Nervous Systemmentioning

confidence: 88%

Transthyretin: a multifaceted protein

Vieira¹,

Saraiva²

2014

BioMolecular Concepts

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Transthyretin is a highly conserved homotetrameric protein, mainly synthetized by the liver and the choroid plexus of brain. The carrier role of TTR is well-known; however, many other functions have emerged, namely in the nervous system. Behavior, cognition, neuropeptide amidation, neurogenesis, nerve regeneration, axonal growth and 14-3-3ζ metabolism are some of the processes where TTR has an important role. TTR aggregates are responsible for many amyloidosis such as familial amyloidotic polyneuropathy and cardiomyopathy. Normal TTR can also aggregate and deposit in the heart of old people and in preeclampsia placental tissue. Differences in TTR levels have been found in several neuropathologies, but its neuroprotective role, until now, was described in ischemia and Alzheimer's disease. The aim of this review is to stress the relevance of TTR, besides its well-known role on transport of thyroxine and retinol-binding protein.

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Section: Ttr In the Nervous Systemmentioning

confidence: 88%

Transthyretin: a multifaceted protein

Vieira¹,

Saraiva²

2014

BioMolecular Concepts

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154

120

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“…In addition, during the last years, several other functions have been associated with this molecule, like its potential role in high-density lipoprotein biology [5], cognition [6], neuroprotection after cerebral ischemia [7] via a megalin dependent pathway [8], modulation of Aβ aggregation [9], regulation of 14-3-3ζ metabolism [10], or glucose homeostasis [11]. However, the existence of genetic point mutations may alter the quaternary structural stability of TTR [12], leading to its dissociation into non-native species which self-assemble and polymerize, ultimately depositing in the extracellular matrix and disrupting normal tissue function [13, 14].…”

Section: Introductionmentioning

confidence: 99%

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Gonçalves

Moreira

Martins

et al. 2017

J Neuroinflammation

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BackgroundIncreasing evidence supports a key role for inflammation in the neurodegenerative process of familial amyloidotic polyneuropathy (FAP). While there seems to be an overactivation of the neuronal interleukin-1 signaling pathway, the immune response is apparently compromised in FAP. Accordingly, little immune cell infiltration is observed around pre-fibrillar or fibrillar amyloid deposits, with the underlying mechanism for this phenomenon remaining poorly understood. Cathepsin E (CtsE) is an important intermediate for antigen presentation and chemotaxis, but its role in the pathogenesis of FAP disease remains unknown.MethodsIn this study, we used both mouse primary macrophages and in vivo studies based on transgenic models of FAP and human samples to characterize CtsE expression in different physiological systems.ResultsWe show that CtsE is critically decreased in bone marrow-derived macrophages from a FAP mouse model, possibly contributing for cell function impairment. Compromised levels of CtsE were also found in injured nerves of transgenic mice and, most importantly, in naïve peripheral nerves, sensory ganglia, murine stomach, and sural nerve biopsies derived from FAP patients. Expression of CtsE in tissues was associated with transthyretin (TTR) deposition and differentially regulated accordingly with the physiological system under study. Preventing deposition with a TTR small interfering RNA rescued CtsE in the peripheral nervous system (PNS). In contrast, the expression of CtsE increased in splenic cells (mainly monocytes) or peritoneal macrophages, indicating a differential macrophage phenotype.ConclusionAltogether, our data highlights the potential of CtsE as a novel FAP biomarker and a possible modulator for innate immune cell chemotaxis to the disease most affected tissues—the peripheral nerve and the gastrointestinal tract.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0891-9) contains supplementary material, which is available to authorized users.

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“…Moreover, it has been described that tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein, zeta (14‐3‐3zeta or YWHAZ) expression levels decreased with aging . Also, Vieira et al, 2013 showed that TTR regulates YWHAZ protein levels and so the absence of TTR correlated with decreased levels of YWHAZ in the hippocampus in young/adult TTR null mice when compared to TTR wild‐type animals, although no changes in gene expression were found …”

Section: Introductionmentioning

confidence: 99%

Familial amyloid polyneuropathy in Portugal: New genes modulating age‐at‐onset

Santos

Coelho

Alves‐Ferreira

et al. 2016

Ann Clin Transl Neurol

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ObjectivesFamilial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age‐at‐onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family‐centered approach.MethodsWe analyzed 62 tagging SNPs from nine genes‐NGAL,MMP‐9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ – in a sample of 318 V30M Portuguese patients (106 families), currently under follow‐up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO.ResultsWe found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early‐ and/or late‐onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP‐9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors.InterpretationThese findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow‐up of mutation carriers and could contribute for development of potential therapeutical targets.

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Transthyretin regulates hippocampal 14‐3‐3ζ protein levels

Cited by 16 publications

References 48 publications

Transthyretin: a multifaceted protein

Transthyretin: a multifaceted protein

Differential expression of Cathepsin E in transthyretin amyloidosis: from neuropathology to the immune system

Familial amyloid polyneuropathy in Portugal: New genes modulating age‐at‐onset

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