Introduction GABARAP - Gamma-Aminobutyric Acid Receptor-Associated Protein. Lipidation of GABARAP GABARAP lipidation is a critical post-translational modification essential for autophagy, a cellular degradation pathway that delivers cytoplasmic components to lysosomes. This process involves the conjugation of GABARAP to phosphatidylethanolamine (PE) in autophagosomal membranes, enabling GABARAP to function in cargo recruitment and membrane biogenesis. The lipidation of GABARAP follows a ubiquitin-like conjugation system that requires multiple enzymes working in sequence. The final step in the sequence is transfer of GABARAP/LC3 (a family of proteins collectively called ATG8) from ATG3 to phosphatidylethanolamine (PE) in the membrane (R1).

8 forms of Vitamin E Vitamin E is a collective term for eight naturally occurring compounds, four tocopherols (α-, β-, γ- and δ-) and four tocotrienols (α-, β-, γ- and δ-), that qualitatively exhibit the biological activities of α-tocopherol. The eight forms of vitamin E are not interconvertible in humans. (R4) Tocopherols alpha-Tocopherol After 2 mo of pill taking, α-tocopherol supplementation increased serum α-tocopherol concentration compared with placebo, but significantly reduced serum γ-tocopherol concentration (R4)

Nrf1 is a master regulator of Proteasomal function Info Gene Code: NFE2L1 Alternative code: TCF11 Full name: Nuclear factor-erythroid 2 p45 subunit-related factor 1 Localisations Endoplasmic Reticulum (ER) The full-length p120 precursor form of NRF1 is cotranslationally inserted into the ER via the classical Sec61-dependent pathway (R1) The p120 NRF1 precursor is cotranslationally inserted into the ER through Sec61. It adopts a type II membrane orientation with most of its mass in the ER lumen and a small N-terminal portion in the cytosol, guided by a hydrophobic TMD.

Lithium Chloride inhibits Proteasome 26S Several studies show that LiCl inhibits 26S: LiCl alone, or in combination with all-trans-retinoic acid, increased cellular levels of ubiquitinated retinoic acid receptor α and markedly reduced chymotryptic-like activity of WEHI-3B D+ 20 S and 26 S proteasome enzymes. (R1) LiCl interacts synergistically with all-trans-retinoic acid, promoting the terminal differentiation of WEHI-3B D(+) cells, a phenomenon partially due to the ability of the monovalent lithium cation to inhibit the proteasome-dependent degradation of retinoic acid receptor alpha protein.

Proteasome: function, genes and structure Good overview here - (R21). Extracellular proteasome Proteasomes were also found in the extracellular CSF, which raises questions of their role. In all patients, extracellular proteasome was found in the CSF. The mean concentration was 24.6 ng/ml. Enzymatic activity of the 20S subunits of proteasomes was positively identified by the fluorescenic subtrate cleavage at a mean of 8.5 fkat/ml. Concentrations of extracellular proteasomes in the CSF, total protein content and Il-6 were uncorrelated.

MAPK inhibits autophagy (by inhibiting ULK1) and promotes inflammation We find that LPS triggers p38α mitogen-activated protein kinase (MAPK)-dependent phosphorylation of ULK1 in microglial cells. This phosphorylation inhibited ULK1 kinase activity, preventing it from binding to the downstream effector ATG13, and reduced autophagy in microglia. Consistently, p38α MAPK activity is required for LPS-induced morphological changes and the production of IL-1β by primary microglia in vitro and in the brain, which correlates with the p38α MAPK-dependent inhibition of autophagy.

N-myristoyltransferase Myristoyl-CoA: protein N-myristoyltransferase (NMT, EC 2.3.1.97), the enzyme catalyzing this stable acylation, has been identified in many organisms. In mammals, two distinct NMT genes referred to as type 1 and 2 have been described. (R3) NMT1 Human NMT1 appears to be targeted predominately to subcellular fractions enriched in ribosomes, consistent with its role as a co-translational protein modifier (R8) NMT2 Protein Myristoylation N-myristoylation is a process involving the covalent attachment of myristate, a 14-carbon saturated fatty acid, to the N-terminal glycine residue of protein.

O‐GlcNAcylation O-GlcNAcylation uses the substrate UDP-GlcNAc, the final product of nutrient flux through the hexosamine biosynthetic pathway (HBP) which integrates amino acid, carbohydrate, fatty acid, nucleotide, and energy metabolism. The HBP fluctuates with cellular metabolism and may be dramatically altered under physiological and pathological conditions. The extent of O-GlcNAcylation can reflect metabolic dynamics in the cell. (R4) Impact on proteins Target Protein Impact NRF1 Protects from ubiquitination, increases activity KEAP1 / NRF2 O‐GlcNAcylation of KEAP1 is required for the efficient ubiquitination and degradation of NRF2 GS Reduces Glycogen Synthase activity by 60% CSE Increases production of H2S by CSE (CTH) Factors affecting O-GlcNAcylation Factor Impact GSK3b Increases activity of OGT by phosphorylating it Glucose deprivation Increases expression of OGT and lowers expression of OGA OGT Three isoforms of OGT Alternative splicing results in three variants of OGT, namely nucleocytoplasmic OGT (ncOGT), mitochondrial OGT(mOGT) and short form OGT(sOGT).

Genotype Quality in Genetics Genotype quality (GQ) is a measure used in genetics to indicate the confidence of a genotype call at a specific genomic position. It represents the probability that the called genotype is incorrect, with higher values indicating greater confidence in the genotype assignment. What is Genotype Quality? When calling variants from sequencing data, genotype quality provides an estimate of how reliable the genotype assignment is at each variant site.

Mapping Quality in Genetics Mapping quality is a measure used in genomics to quantify the confidence that a DNA sequence read is mapped to the correct position in a reference genome. It provides an estimate of the probability that the read alignment is incorrect. A higher mapping quality score indicates a higher likelihood that the read is mapped accurately. What is Mapping Quality? When aligning millions of short DNA sequence reads to a reference genome, there can be ambiguity in where certain reads should map, especially in repetitive regions of the genome.