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Can you try these two questions on Amyloid ?

Can you try these two questions on Amyloid ?

Is it a physiological molecule ?

1.Yes, It is a physiological molecule.

2.No, Amyloid is always pathological.

Where does it gets deposited ?

A .Extracellular*

B. Intracellular

C. Both

Answer : Q 1: A / Q 2: C. It is indeed a physiological molecule in small amounts that help carry hormones across the blood. In pathology, it accumulates in huge amounts. It is a disorder of protein folding, making them thick, stiff , sheets of peptide, hence mis-behaving with adjacent cells, injuring them in the process. This is responsible for the systemic nature of disorder right from the brain to peripheral nerves, Heart, kidneys, liver, spleen, etc. (Ref 1)

(*It should be stressed , majority of deposition occurs in extracellular space.They clog the interstitial space, also can invade the cell, especially in neurons in Alzheimer’s disease . Now we have evidence that Aβ (A beta) get into the myocytes as well. (Troncone L, J Am Coll Cardiol. 2016) Fellows, better say amyloid is primarily extracellular, but, by pressure effect and injury of cell membrane it results in cell death.)

Ultrastructural Organization of Amyloid Fibrils byAtomic Force Microscopy Image source Chamberlain AK, . Biophys J. 2000 Dec;79(6):3282-93.

Can we dissolve it or get rid of it ?

Till now, these disorders has been termed as a degenerative disease with no viable options. Now, we have made a breakthrough. A group of drugs genetically created work by unfolding the proteins by interfering with RNA (SiRNA) that home in on the host liver and help clear these systemic proteostasis, the key pathology in Amyloidosis (TTR).

Patisiran is approved by FDA for peripheral neuropathy and used in cardiac amyloidosis. Patisiran is a siRNA encapsulated within a lipid nanoparticle delivery system for targeted delivery to the liver, the primary source of serum TTR . Once in the liver, siRNA binds to the untranslated region of TTR mRNA and degrades it, inhibiting TTR synthesis. ( Adams D et al NEJM 2018)

Tafamidis is another similar drug. (N Engl J Med 2018; 379:1007-1016)

Final message

We are moving in the right direction in tackling the cell aging, degeneration and cell fibrosis that is behind majority of chronic systemic disorders.(Anti-fibrotic drugs is the next big target Ref: Front. Pharmacol., 31 May 2017 )

Reference

1.Greenwald J, Riek R. Biology of amyloid: structure, function, and regulation. Structure. 2010 Oct 13;18(10):1244-60.

2.Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang CC, Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21.