The mutated enzyme weakens the connections between brain cells that help control movement

In a rare genetic disease that affects the control of body movement, scientists have discovered that a mutation in an enzyme impairs the communication between neurons and the inherent ability to be when we need to run faster, instead of walking, across the street

This disease is spinocerebellar ataxia, or SCA for short.

This enzyme is ELOVL4, which can produce very long fatty acids, and its mutations are known to cause specific SCA 34 types

"We found that the synaptic response was significantly weakened

Although the genetic mutations that cause SCA are different, the changes in cerebellar output and the effect on Purkinje cells seem to be a common problem

Like an air traffic controller in a busy airport, these brain cells obviously monitor many different inputs at the same time, and they are the only neurons that send information from that part of the brain

Purkinje cells get a lot of information from granular cells, which are one of the smallest neurons in the brain but the largest number

The new study of ELOVL4 finds that mutations lead to a significant reduction in the ability of synapses to enable information from Purkinje cells to strengthen the signal, which in this case is vital for coordinated movement, so you can speed up your speed if needed or move your The hand ordered frantically

Deak said their findings point to the important role of ELOVL4 in motor function and synaptic plasticity

They also believe that the communication between key neurons in the cerebellum of patients with sc34 is damaged and asynchronous long before the brain shows obvious signs of degeneration

Dick pointed out that over time, the impaired response between these constantly communicating cells may lead to degeneration of the cerebellum.

But in their sc34 model, the structure of the cerebellum looks normal at 6 months of age, even though the animal model clearly has the expected motor deficits, the scientists report

They found that the synapses were also intact and functioned at a basic level, for example, allowing mice to walk normally, but in these knock-in mice, the usual plasticity or flexibility is lacking

ELOVL4 can make saturated and unsaturated long-chain fatty acids-they are called "long" because they contain a large number of carbon atoms-depending on the tissue in which the enzyme is located

Scientists believe that the weakened synaptic response they found is a quantitative problem: the mutated enzyme produces about 70% of the normal amount of ultra-long-chain fatty acids, which seems to be the threshold for gait problems
.
If the cells are not produced, it can lead to excessive seizures and death, as Dick has seen in other models
.

Their current research includes finding ways to deliver more saturated long-chain fatty acids to the brain
.
Dick said that scientists are applying for a patent to achieve this operation
.
When you produce saturated long-chain fatty acids, they have the consistency of candle wax, and the mouse won’t even digest it, just excrete it, which makes this operation more difficult
.

Scientists say that long-chain fatty acids are essential for life, but their exact role is mostly elusive
.

Deak said: "From our work, we know that they are a very important part of certain cell membranes
.
" For example, the cell membranes of certain excitatory and inhibitory neurons, as well as the cell membranes of skin cells
.
In fact, scientists have proven that when ELOVL4 is missing in the skin, body fluids will seep through the skin, which is our largest natural barrier
.
Deak said that when producing other ELOVL4 mutant mouse models, they must overexpress ELOVL4 in the skin to ensure survival
.

Dick’s research shows that these saturated long-chain fatty acids also like to accumulate and strengthen vesicles, which are tiny mobile compartments that can move within the cell, so they can better reach their destination before fusing with the cell membrane
.
Fusion is necessary for neurotransmission-one of the substances delivered by the vesicles in the brain is a chemical messenger called a neurotransmitter-but uncontrolled fusion is harmful
.

When scientists discovered that mice with two mutant copies of ELOVL4 died of epilepsy, they documented its effects
.
He said that when they made these findings in the laboratory, Saudi Arabia reported that children had the same mutations and problems
.
In fact, it was Deak's research interest in epilepsy that prompted him to further understand the role of long-chain fatty acids
.
He suspects that they also play a role in his other interests: the aging brain and Alzheimer's disease
.

A team led by Dr.
Martin-Paul Agbaga created a rat model of "knock-in" the human disease SCA34, which has been confirmed in a French-Canadian family and three Japanese families
.
In these individuals, skin problems appear shortly after birth until puberty, while movement problems and typical progressive movement problems begin to appear in their 30s
.

Agbaga is the co-corresponding author of this new paper and one of Dick’s long-term collaborators.
He is a vision scientist and cell biologist in the Department of Ophthalmology, University of Oklahoma Health Sciences Center and Dean McGee Eye Institute
.

Dr.
Robert E.
Anderson is a professor of vision research at the Dean McGee Eye Institute, founder of the ELOVL4 research group in Oklahoma, and a global leader in the pathophysiology of retinal lipids.
He is the author of this paper Co-author
.
Dick came to MCG from the University of Oklahoma Health Science Center last year
.

SCA has a wide range of incidences in humans, ranging from 8 to 60 years old.
Symptoms also include poor hand and eye movements and poor language coordination, usually after 18 years of age
.
Deak said that apart from physical therapy, there are currently no good treatment options for SCA patients
.

Article title

W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34