Newly Discovered Protein Connected to Alzheimers Disease Risk – Neuroscience News

Summary: A mutation in the newly discovered SHMOOSE small protein is associated with an increased risk of developing Alzheimers disease.

Source: USC

A mutation in a newly discovered small protein is connected to a significant increase in the risk for Alzheimers disease, expanding the known gene targets for the disease and presenting a new potential avenue for treatment, according to a new USC study.

The protein, called SHMOOSE, is a tiny microprotein encoded by a newly discovered gene within the cells energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is associated with a 20-50 % higher risk for Alzheimers disease across four different cohorts. Nearly a quarter of people of European ancestry have the mutated version of the protein, according to the researchers.

The research appears Wednesday, September 21 in the journalMolecular Psychiatry.

The researchers say that both the substantial risk and high prevalence of this previously unidentified mutation differentiate it from other proteins involved in Alzheimers disease.

Apart from APOE4 the most potent known genetic risk factor for the disease only a limited number of other gene mutations have been identified and these only mildly increased risk by less than 10%.

Also, because the microprotein is approximately the size of the insulin peptide, it can be easily administered, which increases its therapeutic potential.

This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimers disease, focusing on SHMOOSE as a target area, saidPinchas Cohen, professor of gerontology, medicine and biological sciences and senior author of the study.

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.

Brendan Miller, 22 PhD in neuroscience graduate and first author of the study, used big data techniques to identify genetic variations in mitochondrial DNA associated with disease risk. After analyses revealed a gene mutation increased Alzheimers disease risk, brain atrophy, and energy metabolism, Miller and his colleagues discovered that the mutated gene coded for the SHMOOSE microprotein and began studying its mutated and default forms.

The researchers stated SHMOOSE is the first mitochondrial-DNA-encoded microprotein to have been detected using both antibodies and mass spectrometry.

The microprotein appears to modify energy signaling and metabolism in the central nervous system. It was found in mitochondria of neurons and its levels in cerebrospinal fluid correlated with biomarkers of Alzheimers disease.

A variety of cell culture and animal experiments showed that SHMOOSE alters energy metabolism in the brain in part by inhabiting a crucial part of the mitochondria, the inner mitochondrial membrane.

An emerging field of study

Miller said the findings highlights the importance of the relatively new field of microproteins. 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.

The field of microproteins is still so new, Miller said. We dont 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. 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.

USC Leonard Davis researchers are leaders in the study of microproteins, especially those coded within the mitochondrial genome. In 2003, Cohen and his colleagues were one of the three research teams to independently discover theprotein humanin, which appears to have protective health effects in Alzheimers, atherosclerosis and diabetes.

In the past few years, the Cohen Laboratory discovered several other mitochondrial microproteins, including, small humanin-like peptides, orSHLPs, and a microprotein calledMOTS-c,an exercise-mimetic peptide that has entered clinical trials for obesity and fatty liver.

Additional coauthors include Su-Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Thalida E. Arpawong, Eileen Crimmins, Meral A. Tubi, Evan T. Hare, Meredith N. Braskie, La Dcarie-Spain, Scott E. Kanoski, Lu Zhao, Arthur W. Toga, Junxiang Wan, and Kelvin Yen of USC; as well as Joan Vaughan, Jolene Diedrich, and Alan Saghatelian of the Salk Institute for Biological Studies; Nilfer Ertekin-Taner of the Mayo Clinic; and Francine Grodstein and David A. Bennett of the Rush University Medical Center.

Funding: The study was supported by NIH grants P30AG10161, P30AG072975, R01AG15819, R01AG17917, U01AG61356, R01AG069698, RF1AG061834, R01AG068405, P30AG068345, P01AG055369, DK118402, F31 AG059356, and T32 AG00037; as well as The Quebec Research Funds Postdoctoral Fellowship. Intellectual property related to SHMOOSE has been filed by the University of Southern California.

Author: Leigh HopperSource: USCContact: Leigh Hopper USCImage: The image is in the public domain

Original Research: Open access.Mitochondrial DNA variation in Alzheimers disease reveals a unique microprotein called SHMOOSE by Pinchas Cohen et al. Molecular Psychiatry

Abstract

Mitochondrial DNA variation in Alzheimers disease reveals a unique microprotein called SHMOOSE

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimers disease (AD), neuroimaging, and transcriptomic.

We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometrythe first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date.

Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments.

SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption.

Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimers disease, and microproteins.

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Newly Discovered Protein Connected to Alzheimers Disease Risk - Neuroscience News