Cappers That Balance TDP-43 Fibril Blocking with Healthy Transport Granules

Overview

Misfolded fibril forms of the protein TDP-43 have been identified as a likely cause of, or contributor to, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), Motor Neuron Disorder (MND), Chronic Traumatic Encephalopathy (CTE), as well as a fraction of Alzheimer's Disease cases. TDP-43 is best known as a protein that carries RNA instructions for protein synthesis from the nucleus to the cytosol of neurons, but has recently been found to also carry important RNA out into neuronal synapses and axons by forming what are known as 'transport granules' that are designed to deliver material from the neuron cytosol and out to axons. In order for TDP-43 to enter these granules, TDP-43 must partially change its fold, though this change need not go so far as to lead to fibril formation. As a result of learning about this 'balancing act', we have modified our earlier objectives of finding molecules that completely prevented TDP-43 from changing shape, and are now looking for molecules that only block the drastic fibril-forming shape shift. To accomplish this, we are using Gaussian Accelerated Molecular Dynamics simulations to measure the shape stabilizing effect of 'parts' of our successful fibril cappers (found in our early studies) to find new molecules that still cap fibrils but do not stick to healthy, partially-refolded TDP-43 structures.

Competition history

• AJAS 2019 Category not listed

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