Lipidome alterations in human prefrontal cortex during development, aging, and cognitive disorders.

Lipids are essential to brain functions, yet they remain largely unexplored. Here we investigated the lipidome composition of prefrontal cortex gray matter in 396 cognitively healthy individuals with ages spanning 100 years, as well as 67 adult individuals diagnosed with autism (ASD), schizophrenia (SZ), and Down syndrome (DS). Of the 5024 detected lipids, 95% showed significant age-dependent concentration differences clustering into four temporal stages, and resulting in a gradual increase in membrane fluidity in individuals ranging from newborn to nonagenarian. Aging affects 14% of the brain lipidome with late-life changes starting predominantly at 50-55 years of age-a period of general metabolic transition. All three diseases alter the brain lipidome composition, leading-among other things-to a concentration decrease in glycerophospholipid metabolism and endocannabinoid signaling pathways. Lipid concentration decreases in SZ were further linked to genetic variants associated with disease, indicating the relevance of the lipidome changes to disease progression.

Recently Evolved Tumor Suppressor Transcript TP73-AS1 Functions as Sponge of Human-Specific miR-941.

MicroRNA (miRNA) sponges are vital components of posttranscriptional gene regulation. Yet, only a limited number of miRNA sponges have been identified. Here, we show that the recently evolved noncoding tumor suppressor transcript, antisense RNA to TP73 gene (TP73-AS1), functions as a natural sponge of human-specific miRNA miR-941. We find unusually nine high-affinity miR-941 binding sites clustering within 1 kb region on TP73-AS1, which forms miR-941 sponge region. This sponge region displays increased sequence constraint only in humans, and its formation can be traced to the tandem expansion of a 71-nt-long sequence containing a single miR-941 binding site in old world monkeys. We further confirm TP73-AS1 functions as an efficient miR-941 sponge based on massive transcriptome data analyses, wound-healing assay, and Argonaute protein immunoprecipitation experiments conducted in cell lines. The expression of miR-941 and its sponge correlate inversely across multiple healthy and cancerous tissues, with miR-941 being highly expressed in tumors and preferentially repressing tumor suppressors. Thus, the TP73-AS1 and miR-941 duo represents an unusual case of the extremely rapid evolution of noncoding regulators controlling cell migration, proliferation, and tumorigenesis.