Biallelic null variants in PNPLA8 cause microcephaly by reducing the number of basal radial glia.

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.

The Effect of Protocatechuic Acid on Blood Pressure and Oxidative Stress in Glucocorticoid-induced Hypertension in Rat.

Oxidative stress is one of the important mechanisms involved in Dexamethasone (Dex)-induced hypertension. Protocatechuic acid (PCA) is a natural compound with high antioxidant capacity. In this investigation, the effect of pretreatment with PCA was studied in Dex-induced hypertensive male Wistar rats. For induction of hypertension, Dex was injected subcutaneously for 14 days. PCA (50, 100 and 200 mg/kg) was started from 4 days before Dex administration and continued during the test period. Systolic blood pressure (SBP) was recorded using tail-cuff method. Measurement of thymus weight was done as a marker of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were determined in plasma samples. Significant increase in SBP and plasma H2O2 concentration and decrease in FRAP value and in the body and thymus weights were observed in Dex-induced hypertensive rats. PCA dose-dependently prevented hypertension and body weight loss, and reduced plasma H2O2 concentration and increased FRAP values. These results suggest the antihypertensive and antioxidant effects of PCA against Dex-induced hypertension.