Mitochondrial DNA variation in Alzheimer's 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 Alzheimer's disease (AD), neuroimaging, and transcriptomics. 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 spectrometry-the 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, Alzheimer's disease, and microproteins.

Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology.

The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial-derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4-centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid-beta accumulation compared to the wild-type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid-beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4-linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.

Papaya and pineapple juices facilitate rehydration of mummified dermal tissue for fingerprint capture.

Mummified remains pose an issue for forensic scientists as identification of the deceased can be difficult due to extreme shriveling of dermal tissue and a resulting lack of quality fingerprint features. The typical protocols used to address this problem include corrosive chemicals that may further damage the already susceptible tissues. An alternative approach is found in the juice of two fruit species known to contain proteolytically active enzymes that tenderize soft tissues, thereby promoting water uptake. In this study, we saturated mummified fingers in papaya and pineapple juice treatments, followed by syringe-facilitated finger volume distension. After juice saturation, the data showed statistically significant increases in mass and volume of the samples, (papaya: relative mass p < 0.02833, relative volume p < 0.008466; pineapple: relative mass p < 0.01426, relative volume p < 0.04182). The post-treatment tissues were then rehydrated through a hydraulic mechanism that exerted the required turgor for effective fingerprint capture. This novel protocol utilizes fruit-based reagents to rehydrate mummified fingers without risk of corrosive damage, allowing for the restoration of accurate fingerprints and the positive identification of decedents. The value of this protocol lies in its simple implementation, affordability, instrument availability, and time effectiveness.