Identification of protein quality control regulators using a Drosophila model of TPI deficiency.

Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the "common" TPIE105Dmutation, result in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPIsugarkill allele (a.k.a. sgk or M81T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPIsugarkill produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPIsugarkill degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPIsugarkill degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPIsugarkill turnover. Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPIsugarkill may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases.

White matter lipid alterations during aging in the rhesus monkey brain.

The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the differences in lipid composition. Our findings indicate that myelin in the normal aging monkey brain shows diverse lipid changes, which may relate to age-related myelin pathology and could constitute targets for designing nutrient supplements or drugs to rejuvenate the brain's lipidome.

Long-term calorie restriction reduces oxidative DNA damage to oligodendroglia and promotes homeostatic microglia in the aging monkey brain.

Calorie restriction (CR) is a robust intervention that can slow biological aging and extend lifespan. In the brain, terminally differentiated neurons and glia accumulate oxidative damage with age, reducing their optimal function. We investigated if CR could reduce oxidative DNA damage to white matter oligodendrocytes and microglia. This study utilized post-mortem brain tissue from rhesus monkeys that died after decades on a 30 % reduced calorie diet. We found that CR subjects had significantly fewer cells with oxidative damage within the corpus callosum and the cingulum bundle. Oligodendrocytes specifically showed the greatest response to CR with a robust reduction in DNA damage. Additionally, we observed alterations in microglia morphology with CR subjects having a higher proportion of ramified, homeostatic microglia and fewer pro-inflammatory, hypertrophic microglia relative to controls. Furthermore, we determined that the observed attenuation in damaged DNA occurs primarily within mitochondria. Overall, these data suggest that long-term CR can reduce oxidative DNA damage and offer a neuroprotective effect in a cell-type-specific manner in the aging monkey brain.