Research reveals how subtle changes in a microRNA may lead to ALS
Researchers find a tipping point in genetic changes, leading to the development of disease in an animal model

Date:
August 26, 2021
Source:
Salk Institute
Summary:
This latest research on microRNAs (miRNAs), regulatory molecules
that act like brakes to reduce the production of proteins, has
implications for studying and treating the underlying causes of
amyotrophic lateral sclerosis (ALS) and other neurological and
psychiatric disorders. The work could also be applicable to a wide
range of diseases involving changes in gene expression levels,
like cancer.



FULL STORY ==========================================================================
When people think about the connection between genes and disease, they
often envision something that works like a light switch: When the gene
is normal, the person carrying it does not have the disease. If it gets mutated, a switch is flipped, and then they do have it.


==========================================================================
But it's not always that simple. Disease-related genes often have
different degrees to which they are turned on or off. In these cases,
there is a tipping point: With only an incremental biological change
around a critical threshold, a person can go from having no symptoms
to being very sick. The latest research on this topic from the Salk
Institute has implications for studying and treating the underlying
causes of amyotrophic lateral sclerosis (ALS) and other neurological
and psychiatric disorders. The work, which was published in Neuronon
August 26, 2021, could also be applicable to a wide range of diseases
involving changes in gene expression levels, like cancer.

"This is increasingly becoming a new and very interesting direction
for ALS research," says Salk Professor Samuel Pfaff, the paper's senior
author. "Our study is highly revealing in terms of how gene regulation
occurs within neurons. While our experiments were done in mice, we
believe these findings will also apply to humans." A handful of genes
has been found in patients that are associated with ALS, a disease of the
motor neurons that leads to paralysis. What many of these genes have in
common is that they are linked to the manufacture of microRNAs (miRNAs)
-- regulatory molecules that act like brakes to reduce the production of proteins. In the first part of this research, the team did a systematic
review of past studies that profiled microRNA levels in patients with
ALS. They found that across all the studies, the same microRNA, called
miR-218, kept showing up as being lower, but not completely lost, in
people with ALS. They decided to study why particular levels of miR-218
are important for motor neurons to do their job normally.

In a mouse model of ALS, Salk researcher Neal Amin, now a clinical scholar
and postdoctoral researcher at Stanford University, devised a strategy
to finely lower the levels of miR-218 in a controlled way to study the
effects on motor neurons' control of muscle function. Amin found that
there's a critical threshold somewhere between 36 percent and 7 percent
of normal levels that leads to muscle paralysis and death. Above 36
percent, neuromuscular junctions are normal and healthy; below 7 percent, neuromuscular deficits are lethal. The rest of the study was focused on
trying to understand why that was the case.

It turns out that miR-218 regulates the function of about 300 different
genes.

Many of them encode proteins related to how motor neurons grow axons
and send signals to muscle. Once the levels of miR-218 dropped below
36 percent, the way these neurons could signal to muscles dropped off dramatically. The researchers used cutting-edge tools in the lab to
determine how miR-218 was influencing various genes.

"Instead of acting like a simple switch, the molecule miR-218 is
like an orchestra conductor of 300 musicians playing together," Amin
says. "Instead of gradually telling all of the players to dim the volume
of their instruments in unison, it's telling some musicians to play more quietly and others to stop completely. It has a much more dynamic and
complex control over gene function than we ever previously appreciated."
The researchers say that being able to study this fine-tuning in animal
models will allow them to learn much more about how genetic mutations
that reduce gene expression put patients at risk for developing brain disorders. This could eventually lead to new treatments that get at the
heart of the biological changes that lead to disease. The research not
only has implications for ALS, but for other diseases of the nervous
system, including schizophrenia, which has also been associated with
changes in the expression level of microRNAs.

"We think that these processes may also take place in other
diseases related to genes and aging, including cancer," says
Pfaff, who holds the Benjamin H. Lewis Chair at Salk. "Having a
new way to create animal models of how genetic disease begins
and how it progresses will allow us to get at the underlying
mechanisms and a deeper understanding of these complex activities." ========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Neal D. Amin, Gokhan Senturk, Giancarlo Costaguta, Shawn Driscoll,
Brendan O'Leary, Dario Bonanomi, Samuel L. Pfaff. A hidden
threshold in motor neuron gene networks revealed by modulation of
miR-218 dose.

Neuron, 2021; DOI: 10.1016/j.neuron.2021.07.028 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210826111649.htm

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