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Glutathione is a remarkably functional molecule with diverse features, which include being an antioxidant, a regulator of DNA synthesis and repair, a protector of thiol groups in proteins, a stabilizer of cell membranes, and a detoxifier of xenobiotics. Glutathione exists in two states—oxidized and reduced. Under normal physiological conditions of cellular homeostasis, glutathione remains primarily in its reduced form. However, many metabolic pathways involve oxidization of glutathione, resulting in an imbalance in cellular homeostasis. Impairment of glutathione function in the brain is linked to loss of neurons during the aging process or as the result of neurological diseases such as Huntington’s disease, Parkinson’s disease, stroke, and Alzheimer’s disease. The exact mechanisms through which glutathione regulates brain metabolism are not well understood. In this review, we will highlight the common signaling cascades that regulate glutathione in neurons and glia, its functions as a neuronal regulator in homeostasis and metabolism, and finally a mechanistic recapitulation of glutathione signaling. Together, these will put glutathione’s role in normal aging and neurological disorders development into perspective.

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial 1 . Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins 2 . However, the anatomical and cellular complexity of developing human tissues 3 —particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus—makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development. Multi-omic mapping shows that group 3 and group 4 medulloblastomas have a common, human-specific developmental origin in the cerebellar rhombic lip, providing a basis for their ambiguous molecular features and overlapping anatomical location, and for the difficulty of modelling these tumours in mice.

Preterm birth and its complications and the associated adverse factors, including brain hemorrhage, inflammation, and the side effects of medical treatments, are the leading causes of neurodevelopmental disability. Growing evidence suggests that preterm birth affects the cerebellum, which is the brain region involved in motor coordination, cognition, learning, memory, and social communication. The cerebellum is particularly vulnerable to the adverse effects of preterm birth because key cerebellar developmental processes, including the proliferation of neural progenitors, and differentiation and migration of neurons, occur in the third trimester of a human pregnancy. This review discusses the negative impacts of preterm birth and its associated factors on cerebellar development, focusing on the cellular and molecular mechanisms that mediate cerebellar pathology. A better understanding of the cerebellar developmental mechanisms affected by preterm birth is necessary for developing novel treatment and neuroprotective strategies to ameliorate the cognitive, behavioral, and motor deficits experienced by preterm subjects.

Model organism studies have demonstrated that cell fate specification decisions play an important role in normal brain development. Their role in human neurodevelopmental disorders, however, is poorly understood, with very few examples described. The cerebellum is an excellent system to study mechanisms of cell fate specification. Although signals from the isthmic organizer are known to specify cerebellar territory along the anterior–posterior axis of the neural tube, the mechanisms establishing the cerebellar anlage along the dorsal–ventral axis are unknown. Here we show that the gene encoding pancreatic transcription factor PTF1A, which is inactivated in human patients with cerebellar agenesis, is required to segregate the cerebellum from more ventral extracerebellar fates. Using genetic fate mapping in mice, we show that in the absence of Ptf1a , cells originating in the cerebellar ventricular zone initiate a more ventral brainstem expression program, including LIM homeobox transcription factor 1 beta and T-cell leukemia homeobox 3. Misspecified cells exit the cerebellar anlage and contribute to the adjacent brainstem or die, leading to cerebellar agenesis in Ptf1a mutants. Our data identify Ptf1a as the first gene involved in the segregation of the cerebellum from the more ventral brainstem. Further, we propose that cerebellar agenesis represents a new, dorsal-to-ventral, cell fate misspecification phenotype in humans.

The extent of neocortical gyrification is an important determinant of a species’ cognitive abilities, yet the mechanisms regulating cortical gyrification are poorly understood. We uncover long-range regulation of this process originating at the telencephalic dorsal midline, where levels of secreted Bmps are maintained by factors in both the neuroepithelium and the overlying mesenchyme. In the mouse, the combined loss of transcription factors Lmx1a and Lmx1b, selectively expressed in the midline neuroepithelium and the mesenchyme respectively, causes dorsal midline Bmp signaling to drop at early neural tube stages. This alters the spatial and temporal Wnt signaling profile of the dorsal midline cortical hem, which in turn causes gyrification of the distal neocortex. Our study uncovers early mesenchymal-neuroepithelial interactions that have long-range effects on neocortical gyrification and shows that lissencephaly in mice is actively maintained via redundant genetic regulation of dorsal midline development and signaling. The contribution of long-range signaling to cortical gyrification remains poorly understood. In this study, authors demonstrate that the combined genetic loss of transcription factors Lmx1a and Lmx1b, expressed in the telencephalic dorsal midline neuroepithelium and head mesenchyme, respectively, induces gyrification in the mouse neocortex

Development of the nervous system depends on signaling centers – specialized cellular populations that produce secreted molecules to regulate neurogenesis in the neighboring neuroepithelium. In some cases, signaling center cells also differentiate to produce key types of neurons. The formation of a signaling center involves its induction, the maintenance of expression of its secreted molecules, and cell differentiation and migration events. How these distinct processes are coordinated during signaling center development remains unknown. By performing studies in mice, we show that Lmx1a acts as a master regulator to orchestrate the formation and function of the cortical hem (CH), a critical signaling center that controls hippocampus development. Lmx1a co-regulates CH induction, its Wnt signaling, and the differentiation and migration of CH-derived Cajal–Retzius neurons. Combining RNAseq, genetic, and rescue experiments, we identified major downstream genes that mediate distinct Lmx1a-dependent processes. Our work revealed that signaling centers in the mammalian brain employ master regulatory genes and established a framework for analyzing signaling center development.

The transcription factor Lmx1a is widely expressed during early inner ear development, and mice lacking Lmx1a expression exhibit fusion of cochlear and vestibular hair cells and fail to form the ductus reuniens and the endolymphatic sac. Lmx1a dreher ( Lmx1a dr/dr ), a recessive null mutation, results in non-functional Lmx1a expression, which expands from the outer sulcus to the stria vascularis and Reissner’s membrane. In the absence of Lmx1a , we observe a lack of proteins specific to the stria vascularis, such as BSND and KCNQ1 in marginal cells and CD44 in intermediate cells. Further analysis of the superficial epithelial cell layer at the expected stria vascularis location shows that the future intermediate cells migrate during embryonic development but subsequently disappear. Using antibodies against pendrin ( Slc26a4 ) in Lmx1a knockout (KO) mice, we observe an expansion of pendrin expression across the stria vascularis and Reissner’s membrane. Moreover, in the absence of Lmx1a expression, no endocochlear potential is observed. These findings highlight the critical role of Lmx1a in inner ear development, particularly in the differentiation of cochlear and vestibular structures, the recruitment of pigment cells, and the expression of proteins essential for hearing and balance.

Preterm birth, a major contributor to infant mortality and morbidity, impairs development of the cerebellum, the brain region involved in cognitive processing and motor function. Previously, we showed that at term-equivalent age, preterm pigs that received formula supplemented with docosahexaenoic acid (DHA) esterified to phosphatidylserine (PS) had cerebellar weights similar to those of newborn term pigs and were heavier than control preterm pigs. However, whether PS-DHA promotes the development of specific cerebellar cell populations or enhances key developmental processes remains unknown. Here we investigated the effects of the PS-DHA on development of the cerebellum in preterm pigs delivered via caesarean section and reared for ten days on a milk replacer with either PS-DHA (experimental group) or sunflower oil (control group). Upon necropsy, key cerebellar populations were analyzed using immunohistochemistry. Consumption of PS-DHA was associated with the expansion of undifferentiated granule cell precursors and increased proliferation in the external granule cell layer (EGL). Preterm pigs that received PS-DHA also had significantly fewer apoptotic cells in the internal granule cell layer (IGL) that contains differentiated granule neurons. PS-DHA did not affect the number of differentiating granule cells in the inner EGL, thickness of the inner EGL, density of Purkinje cells, or Bergmann glial fibers, or diameter of Purkinje cells. Thus, PS-DHA may support cerebellar development in preterm subjects by enhancing proliferation of granule cells, a process specifically inhibited by preterm birth, and increasing the survival of granule cells in the IGL. These findings suggest that PS-DHA is a promising candidate for clinical studies directed at enhancing brain development.

An important part of the central nervous system (CNS), the cerebellum is involved in motor control, learning, reflex adaptation, and cognition. Diminished cerebellar function results in the motor and cognitive impairment observed in patients with neurodegenerative disorders such as Alzheimer’s disease (AD), vascular dementia (VD), Parkinson’s disease (PD), Huntington’s disease (HD), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia (FRDA), and multiple sclerosis (MS), and even during the normal aging process. In most neurodegenerative disorders, impairment mainly occurs as a result of morphological changes over time, although during the early stages of some disorders such as AD, the cerebellum also serves a compensatory function. Biological aging is accompanied by changes in cerebellar circuits, which are predominantly involved in motor control. Despite decades of research, the functional contributions of the cerebellum and the underlying molecular mechanisms in aging and neurodegenerative disorders remain largely unknown. Therefore, this review will highlight the molecular and cellular events in the cerebellum that are disrupted during the process of aging and the development of neurodegenerative disorders. We believe that deeper insights into the pathophysiological mechanisms of the cerebellum during aging and the development of neurodegenerative disorders will be essential for the design of new effective strategies for neuroprotection and the alleviation of some neurodegenerative disorders.

Inflammation and an increase in antioxidant responses mediated by oxidative stress play an important role in the pathogenesis of acute liver injury (ALI). We utilized in silico prediction of biological activity spectra for substances (PASS) analysis to estimate the potential biological activity profile of deethylated ethoxyquin (DEQ) and hypothesized that DEQ exhibits antioxidant and anti-inflammatory effects in a rat model of carbon tetrachloride (CCl4)-induced ALI. Our results demonstrate that DEQ improved liver function which was indicated by the reduction of histopathological liver changes. Treatment with DEQ reduced CCl4-induced elevation of gene expression, and the activity of antioxidant enzymes (AEs), as well as the expression of transcription factors Nfe2l2 and Nfkb2. Furthermore, DEQ treatment inhibited apoptosis, downregulated gene expression of pro-inflammatory cytokines (Tnf and Il6), cyclooxygenase 2 (Ptgs2), decreased glutathione (GSH) level and myeloperoxidase (MPO) activity in rats with ALI. Notably, DEQ treatment led to an inhibition of CCl4-induced NLRP3-inflammasome activation which was indicated by the reduced protein expression of IL-1β, caspase-1, and NLRP3 in the liver. Our data suggest that DEQ has a hepatoprotective effect mediated by redox-homeostasis regulation, NLRP3 inflammasome, and apoptosis inhibition, which makes that compound a promising candidate for future clinical studies.