Newly discovered protein connected to Alzheimer’s disease risk

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Greyhound
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Newly discovered protein connected to Alzheimer’s disease risk

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A mutation in the small protein SHMOOSE is associated with Alzheimer’s risk and highlights a possible target for treatment.
Peer-Reviewed Publication

University of Southern California

A mutation in a newly discovered small protein is connected to a significant increase in the risk for Alzheimer’s 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 cell’s energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is associated with a 20-50 % higher risk for Alzheimer’s 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 journal Molecular Psychiatry.

The researchers say that both the substantial risk and high prevalence of this previously unidentified mutation differentiate it from other proteins involved in Alzheimer’s 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 Alzheimer's disease, focusing on SHMOOSE as a target area,” said Pinchas 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 Alzheimer’s 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 Alzheimer’s 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 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. 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 the protein humanin, which appears to have protective health effects in Alzheimer’s, atherosclerosis and diabetes. In the past few years, the Cohen Laboratory discovered several other mitochondrial microproteins, including, small humanin-like peptides, or SHLPs, and a microprotein called MOTS-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, Léa Décarie-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; Nilüfer Ertekin-Taner of the Mayo Clinic; and Francine Grodstein and David A. Bennett of the Rush University Medical Center.

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.

https://www.eurekalert.org/news-releases/964920
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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Here's another article about SHMOOSE from Being Patient.

https://www.beingpatient.com/shmoose-in ... iscovered/

With its connection to mitochondrial function, this seems like one that could lead to treatments to overcome brain energy metabolism problems. Feels like one to watch for sure.

Here's a link to the abstract. The article is behind a paywall. The snp in question is rs2853499, which was in my older 23andme results. Snpedia suggests that A is the mutation, however, I'd need to read the full paper to be sure.

https://www.nature.com/articles/s41380-022-01769-3
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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“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.”
How do you think it would be given as an analog?
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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SusanJ wrote: Sat Oct 29, 2022 9:31 am Here's another article about SHMOOSE from Being Patient.

https://www.beingpatient.com/shmoose-in ... iscovered/

With its connection to mitochondrial function, this seems like one that could lead to treatments to overcome brain energy metabolism problems. Feels like one to watch for sure.

Here's a link to the abstract. The article is behind a paywall. The snp in question is rs2853499, which was in my older 23andme results. Snpedia suggests that A is the mutation, however, I'd need to read the full paper to be sure.

https://www.nature.com/articles/s41380-022-01769-3
For those who want to try to understand a very dense article, you can rent it online (with no download or copying features) for about $8 by following the link to Readcube. But doing so left me with lots of questions, since I don't have a Ph.D. Like you, Susan, I assumed that rs2853499 GG was "normal" variant, with about 75% of European Ancestry people having that and about 25% having the AA allele, which I assumed was the "risk" variant. SNpedia shows the A allele as
"One of the 3 SNPs that defines Mitochondrial Haplogroup U and its descendants.
Rs2853499

Haplogroups U and K are mentioned in the article as showing an increased risk of AD in the large UK Biobank and ADNI (Alzheimer's Disease Neuroimaging Initiative) cohorts followed for years. That would seem to confirm that the A allele, carried by the U/K haplotype, is the risk. The G allele of Rs2853499 is listed as "not U/K" on Snpedia.

But then I found this sentence: "Rs2853499 (henceforth referred to as SHMOOSE.D47N changes the 47th amino acid from glutamine to aspartic acid" which seems to suggest that the particular mitochondria in either form might be a risk. On the plus side, the research, which included only data from people in the UK and US, found that this SMOSH.D47N appears to protect against amyloid beta accumulation. On the negative side, it is associated with P-tau 181 accumulation and several areas of changes in brain structure. Once more proving that many roads (and genes) affect Alzheimer's and other dementia risk.
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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Plumster wrote:How do you think it would be given as an analog?
That's way beyond my pay grade.

I'm mostly interested because this group is looking at something other than amyloid beta or tau as a target for treatment.
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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I'm giving myself a little pat on the back, because for years, since before this forum, I've had a strong hunch that mtDNA would be involved in Alzheimer's, and I could never understand why it doesn't came up as a research subtopic anywhere. My mother and I have the A allele and are mtDNA haplogroup K. She was apoe 3,3 while the AD is on her side of the family. She also has another risk gene, but this one is stronger. However, 23andMe is only showing one result, ie, one A without showing what the paired result is. Maybe mtDNA isn't paired the same way, or doesn't produce heterozygous results, so they only report one result? I look forward to confirmation as to which result is the risk result, but I think it's A (?).
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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circular wrote:However, 23andMe is only showing one result, ie, one A without showing what the paired result is. Maybe mtDNA isn't paired the same way, or doesn't produce heterozygous results, so they only report one result?
Here's your answer about pairing, from Wikipedia:
The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The heavy strand is rich in guanine and encodes 12 subunits of the oxidative phosphorylation system, two ribosomal RNAs (12S and 16S), and 14 transfer RNAs (tRNAs). The light strand encodes one subunit, and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 protein subunits, all of which are involved in the oxidative phosphorylation process.[29][30]
https://en.wikipedia.org/wiki/Mitochondrial_DNA

For a graphic that underscores there are no matched pairs between strands, see this graphic from the same page.
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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Has there been any study or update on what having this mutation along with e4/e4 does in regards to risk? Is it just even more elevated?
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Re: Newly discovered protein connected to Alzheimer’s disease risk

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AllTheFeels wrote: Sun Apr 16, 2023 5:48 pm Has there been any study or update on what having this mutation along with e4/e4 does in regards to risk? Is it just even more elevated?
One of the benefits of following studies on this site is also one of the risks--what we call "going down rabbit holes" of worry about yet another possible risk factor.

This discovery only recently was found after using computers to detect small, but real changes in risk from common variants in genes. This particular one is carried on mitochondria, an ancient type of DNA that we inherit from our mothers through our X chromosome, whether we are male or female.

This is sort of like finding a needle in a haystack: It's exciting to researchers because it might be provide what they call "A novel (new) target for therapy". Every researcher I have heard talks of a day when Alzheimer's prevention will be like cancer treatment:
  • lifestyle strategies (and public health support) to improve health and greatly reduce risk
  • early and regular screening for those with possible higher genetic risk
  • accurate early diagnosis
  • many personalized treatment options to root out, counteract or fix the causes
They all believe we are moving fast towards that day, with a high degree of confidence already in prevention or reduction of risk and early diagnosis.

For now, we can trust that our prevention efforts are known to have a LARGE effect on risk. So don't worry about this new, and not-yet fully understood discovery.
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