Non-Cell-Autonomous Neurotoxicity in Parkinson's Disease Mediated by Astroglial α-Synuclein.

Non-cell-autonomous effects on neuronal cells are considered to be involved in the pathogenesis of neurodegenerative diseases but have yet to be mechanistically proven. In this issue of Stem Cell Reports, di Domenico et al. provide direct evidence that α-synuclein transferred from astrocytes exerts non-cell-autonomous neuronal dysfunction on dopaminergic neurons in Parkinson's disease (PD).

T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease.

Parkinson disease (PD) is a progressive neurological disease caused by selective degeneration of dopaminergic (DA) neurons in the substantia nigra. Although most cases of PD are sporadic cases, familial PD provides a versatile research model for basic mechanistic insights into the pathogenesis of PD. In this study, we generated DA neurons from PARK2 patient-specific, isogenic PARK2 null and PARK6 patient-specific induced pluripotent stem cells and found that these neurons exhibited more apoptosis and greater susceptibility to rotenone-induced mitochondrial stress.

Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors.

Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE-neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities.

DNA Methylome Analysis Identifies Transcription Factor-Based Epigenomic Signatures of Multilineage Competence in Neural Stem/Progenitor Cells.

Regulation of the epigenome during in vivo specification of brain stem cells is still poorly understood. Here, we report DNA methylome analyses of directly sampled cortical neural stem and progenitor cells (NS/PCs) at different development stages, as well as those of terminally differentiated cortical neurons, astrocytes, and oligodendrocytes. We found that sequential specification of cortical NS/PCs is regulated by two successive waves of demethylation at early and late development stages, which are responsible for the establishment of neuron- and glia-specific low-methylated regions (LMRs), respectively.

Prenatal exposure to suberoylanilide hydroxamic acid perturbs corticogenesis.

Suberoylanilide hydroxamic acid (SAHA) is one of the epidrugs developed for cancer treatment that works epigenetically by inhibiting histone deacetylases (HDACs). SAHA has been reported to diffuse across the placenta and found in fetal plasma in preclinical study, implying that it can influence fetus if taken by pregnant cancer patients. However, report regarding this aspect and the study of in utero HDAC inhibition by SAHA especially on fate specification of neural stem/progenitor cells within the developing mammalian cortex, is yet unavailable.

Epigenetic regulation of neural stem cell fate during corticogenesis.

The cerebral cortex comprises over three quarters of the brain, and serves as structural basis for the sophisticated perceptual and cognitive functions. It develops from common multipotent neural stem cells (NSCs) that line the neural tube. Development of the NSCs encompasses sequential phases of progenitor expansion, neurogenesis, and gliogenesis along with the progression of developmental stages.