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Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
Published on: June 9, 2018
Decreased expression of S100A8/A9 in V30M related ATTRv amyloidosis
João Moreira1,2, Sofia Martins1, Margarida Saraiva3
1Molecular Neurobiology Group, Porto, Portugal.
Introduction:
Hereditary Transthyretin Amyloidosis is a rare, progressive and life-threatening systemic disease with predominant peripheral and autonomic nervous system involvement caused by mutation of the transthyretin protein. The most common TTR mutation regarding to ATTRv is a substitution of a Methionine for a Valine at position 30 that predisposes TTR to form aggregates and fibrils.
Methods:
S100A8 protein levels were measured in plasma samples from ATTRV30M patients and healthy donors. Additionally, S100A8/9 levels were measured in Schwann cells after incubation with human WT or V30M TTR. Moreover, bone marrow derived macrophages of either genetic background were generated and the expression of S100A8/9 was measured in response to toll like receptors agonists.
Results:
S100A8/A9 mRNA levels are decreased in HSF V30M mice as compared with the WT. Moreover, S100A8 protein levels were found downregulated in plasma samples from ATTRV30M patients. Furthermore, we provide evidence for a dysregulated S100 expression by Schwann cells in response to TTRV30M and by mutated macrophages in response to toll like receptors agonists.
Conclusion:
The presence of TTRV30M impacts S100 expression, possibly contributing to the impaired immune activation of Schwann cells in nerves from ATTRV30M patients. This may be linked to the diminished immune cellular infiltration in these nerves, contributing in this way for the neuronal dysfunction present in the disease.
Insights
Hereditary transthyretin amyloidosis (ATTRv) involves mutated transthyretin protein (TTRV30M). This study found that TTRV30M dysregulates S100A8/A9 expression in patients, potentially impairing nerve immune responses.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Hereditary Transthyretin Amyloidosis (ATTRv) is a progressive, life-threatening disease caused by transthyretin (TTR) gene mutations.
- The most common mutation, TTRV30M, leads to TTR aggregation and fibril formation, primarily affecting the peripheral and autonomic nervous systems.
Purpose of the Study:
- To investigate the role of S100A8/A9 protein in the pathogenesis of ATTRv.
- To explore the impact of the TTRV30M mutation on S100A8/A9 expression in relevant cell types.
Main Methods:
- Measured S100A8 protein levels in plasma from ATTRV30M patients and healthy donors.
- Assessed S100A8/A9 levels in Schwann cells and macrophages in response to TTRV30M and other stimuli.
- Analyzed S100A8/A9 mRNA levels in V30M mice.
Main Results:
- S100A8/A9 mRNA levels were decreased in V30M mice compared to wild-type.
- S100A8 protein levels were downregulated in plasma from ATTRV30M patients.
- Evidence of dysregulated S100 expression by Schwann cells and macrophages in response to TTRV30M was observed.
Conclusions:
- The TTRV30M mutation impacts S100 expression, potentially contributing to impaired Schwann cell immune activation in ATTRv patients.
- This dysregulation may be linked to reduced immune cell infiltration in nerves, exacerbating neuronal dysfunction in ATTRv.
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