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UK funding (£154,045): Small molecule modulators of lncRNA NEAT1_2: A novel approach to enhancing the endogenous neuroprotective response in amyotrophic lateral sclerosis Ukri1 Apr 2022 UK Research and Innovation, United Kingdom
Overview
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Small molecule modulators of lncRNA NEAT1_2: A novel approach to enhancing the endogenous neuroprotective response in amyotrophic lateral sclerosis
| Abstract | Amyotrophic lateral sclerosis (ALS) is a type of motor neuron disease in which the nerve cells (motor neurons) that control the muscles degenerate and die. This causes in a decline in the ability of the patient to conduct everyday activities, with the progressive loss of function of the muscles responsible for breathing ultimately resulting in the patient dying of respiratory failure. Although in most cases the cause of ALS is unknown, in a small number of patients, the disease is caused by changes in the genes that encode a variety of different proteins. However, despite the different causes of ALS, a common feature in surviving motor neurons is the presence within the nucleus of structures called paraspeckles. These structures are thought to be a normal response to neuronal stress and are therefore considered to be neuroprotective. Consequently, it is hypothesised that increasing the number of paraspeckles should enhance the protection against the cellular stressors and thereby reduce the death of motor neurons in ALS. A central component of the neuroprotective paraspeckle is NEAT1_2, an RNA that does not code for any protein (known as a long non-coding RNA or lncRNA). This molecule acts as a magnet which attracts proteins which stick to NEAT1_2 to form the mature paraspeckle. Our hypothesis is that if we can increase the amount of NEAT1_2 then the number of paraspeckles and resultant neuroprotective effects in ALS motor neurons will also be increased. RNA molecules are generally relatively shapeless which means it is difficult to identify compounds that can bind to them and alter their function. However, NEAT1_2 contains a highly structured region called the 'triple helix' which is amenable to the binding of small molecules. The binding of compounds to such structured regions is a very innovative approach to regulating the function of RNAs, and validation that this strategy can be successful has recently been demonstrated with another lncRNA, MALAT1. In this project we aim to identify compounds that bind to the triple helix of NEAT1_2 with the aim of stabilising this lncRNA. This should increase the amount of NEAT1_2 in the nuclei of motor neurons which will in turn seed the formation of an increased number of neuroprotective paraspeckles in ALS and, potentially, other neurodegenerative disorders, thereby defining a new class of neuroprotective, disease-modifying drugs. |
| Category | Intramural |
| Reference | MC_PC_MR/W031647/1 |
| Status | Closed |
| Funded period start | 01/04/2022 |
| Funded period end | 31/08/2024 |
| Funded value | £154,045.00 |
| Source | https://gtr.ukri.org/projects?ref=MC_PC_MR%2FW031647%2F1 |
Participating Organisations
| CARDIFF UNIVERSITY |
The filing refers to a past date, and does not necessarily reflect the current state. The current state is available on the following page: Cardiff University, Cardiff.