The amyloidoses comprise a spectrum of acquired and hereditary diseases caused by the deposition of characteristic fibrillar material in various organs and tissues throughout the body. In hereditary amyloidoses, different proteins have been involved, including transthyretin (TTR). The most common TTR mutation associated with familial amyloid polyneuropathy (FAP) is V30M in which valine is replaced by a methionine in position 30 of the polypeptide chain. More than 120 amyloidogenic TTR mutations have been described. Besides peripheral and autonomic neuropathy, cardiomyopathy, carpal tunnel syndrome or amyloid deposition in the leptomeninges are clinical features associated with TTR amyloidosis. The cause of this life threatening pathology is misfolding and extracellular deposition of mutant TTR as early non-fibrillar deposits and later as amyloid, triggering inflammatory and oxidative stress pathways and extracellular matrix metalloproteinase upregulation ultimately leading to apoptosis.
Using a pre-clinical transgenic mouse model carrying the V30M-TTR mutation in a HSF-1 deficient background we investigated the efficiency of several compounds such as (i) interference RNA for liver TTR gene silencing; (ii) stabilizers of V30M-TTR; (iii) Doxycycline-tauroursocholic acid (Doxy-TUDCA); and (iv) Anakinra, a Il-1beta antagonist. All these compounds are able to decrease TTR deposition and associated tissue biomarkers. TTR deposition in pre-clinical models of the disease serve to unfold mechanisms of this disease and will be discussed, in particular signalling pathways triggered in the peripheral nervous system.
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