Scientists identify gene mutation that raises risk of Alzheimer’s

By Mark Waghorn via SWNS

A gene mutation that raises the risk of Alzheimer's by up to 50 percent has been identified by scientists from a British database.

It produces a tiny chemical, or microprotein, called SHMOOSE. One-in-four people of European ancestry are carriers.

The finding offers hope of a screening program- and an effective drug, says the American research team.

It's based on brain scans of 18,330 members of the UK Biobank - a database containing in-depth genetic and health information from half a million Britons.

A quarter (25 percent) had the variant. It affects neurons that control memory, emotions and behavior.

"This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer's disease, focusing on SHMOOSE as a target area," said senior author Professor Pinchas Cohen, of the University of Southern California.

"Administration of SHMOOSE analogs in individuals who carry the mutation and produce the mutant protein may prove to have benefit in neurodegenerative and other diseases of aging."

An analog is a drug having a structure similar to that of another compound - but differing in respect of a certain component.

The variant described in Molecular Psychiatry lurks in energy-producing mitochondria - the 'power stations' of cells.

Big data techniques, including artificial intelligence, found it increased Alzheimer's risk by 20 to 50 percent - across four different study populations.

The protein appears to alter energy signalling and metabolism in the central nervous system - shrinking the brain.

It was found in mitochondria of neurons. Levels in cerebrospinal fluid also correlated with signs, or biomarkers of Alzheimer's.

Experiments on lab rats and human cells grown in the lab showed SHMOOSE inhabits a crucial part of the mitochondria - the inner membrane.

"In four cohorts, individuals with SHMOOSE had increased risk for Alzheimer's," Cohen said.

"Carriers also showed greater damage over age in medial temporal areas such as the parahippocampus, entorhinal cortex and anterior and parietal cingulate cortex.

"The medial temporal cortex and parietal cingulate cortex are known to be vulnerable in Alzheimer's disease and the pathological damage likely appears years before clinical symptoms."

First author Brendan Miller, a PhD neuroscience graduate, said microproteins represent a fresh area of research. The findings highlight their importance.

"The field of microproteins is still so new. We don't yet know how many microprotein genes are even functional and the cost to study a potential microprotein one-by-one from a list of thousands is just too expensive and inefficient," he said.

"The approach my colleagues and I used to detect SHMOOSE shows the power of integrating big genetics data with molecular and biochemical techniques to discover functional microproteins."

Dozens of genes are known to be involved in Alzheimer's - the most potent named APOE4. Two copies increase a person's risk twelvefold.

But SHMOOSE could be the next most significant to date. Most others increase risk by less than 10 percent.

What is more, it is about the size of the insulin peptide linked to diabetes making administration easy, and improving therapeutic potential.

It is the first mitochondrial-DNA-encoded microprotein to have been detected using both antibodies and a scanning technique called mass spectrometry.

For decades, scientists have studied biology mostly by considering a set of 20,000 large protein-coding genes.

However, new technology has highlighted hundreds of thousands of potential genes that encode smaller microproteins.

"Mitochondrial-encoded microproteins are a potential part of Alzheimer's disease that have not been heavily studied," Cohen said.

"Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease and microproteins."

Globally, the number of cases of Alzheimer's and other forms of dementia will triple to more than 150 million by 2050.

Currently they affect more than 940,000 people in the UK, a figure that will reach two million within three decades. There is no cure. An effective drug is a 'holy grail' of medical research.

The researchers are leaders in the study of microproteins, especially those coded within the mitochondrial genome.

In 2003, Cohen and colleagues were one of three research teams to independently discover the protein humanin.

It appears to protect against Alzheimer’s, hardening of the arteries and diabetes. In the past few years, his laboratory has discovered several other mitochondrial proteins.

They include small humanin-like peptides, or SHLPs, and a microprotein called MOTS-c, an exercise mimicking compound in clinical trials for obesity and fatty liver disease.