Mitochondria, the cell's powerhouse, produce ATP and contain Mitochondrial DNA encoding microproteins like Humanin. Research points to microproteins' role in age-related conditions, including Alzheimer's disease. Alzheimer's, a progressive neurological disorder, causes brain atrophy and cell death. In the US, 5.8 million people aged 65 and older have Alzheimer's, and worldwide, 60% to 70% of dementia cases are due to Alzheimer's, with no cure.
Recently, Cohen's lab at USC discovered the Humanin microprotein in 2003, and a new mitochondrial microprotein linked to Alzheimer's risk, SHMOOSE. In Molecular Psychiatry, their study revealed that 1 in 4 people of European ancestry have a mutated version of SHMOOSE. First author Brendan Miller, Ph.D., used ADNI's database, finding an Alzheimer's and brain atrophy-associated mutation in mitochondrial SNP (rs2853499), creating the SHMOOSE protein. Isolated from nerve cells' mitochondria using immunoprecipitation, two unique SHMOOSE microprotein fragments were identified using mass spectrometry, a first for detecting mitochondrially encoded microproteins.
The study revealed mutated protein
The study was led by Brendan Miller, Ph.D., who analyzed mitochondrial DNA data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. They identified a mutated mitochondrial SNP (rs2853499) linked to Alzheimer's and brain atrophy, resulting in the discovery of SHMOOSE microprotein. Using immunoprecipitation, SHMOOSE microproteins were isolated from nerve cells' mitochondria, and mass spectrometry detected two unique protein fragments, a first for mitochondrially encoded microproteins.
Subsequent studies on mice and cell cultures integrated SHMOOSE protein into mice brains, observing its activity in the hypothalamus region. Unmutated microproteins were also found to impact mitochondrial metabolism. SHMOOSE microprotein accumulates in mitochondrial nerve cells, binding to Mitofilin and influencing mitochondrial gene expression and oxygen consumption. The mutated version has different effects on gene expression and oxygen consumption.
Dr. Pinchas Cohen, the senior author, highlighted the potential of SHMOOSE microprotein as a target area for precision medicine-based Alzheimer's treatments. Administering SHMOOSE analogs to individuals with the mutant protein may have advantages in neurodegenerative and aging-related disorders.
Follow the Author on MedBound: Sonam Mhavale (@sonammhavale)
