Increased Anxiety-Related Behavior, Impaired Cognitive Function and Cellular Alterations in the Brain of Cend1-deficient Mice

Cend1 is a neuronal-lineage specific modulator involved in coordination of cell cycle exit and differentiation of neuronal precursors. We have previously shown that Cend1−/− mice show altered cerebellar layering caused by increased proliferation of granule cell precursors, delayed radial granule cell migration and compromised Purkinje cell differentiation, leading to ataxic gait and deficits in motor coordination. To further characterize the effects of Cend1 genetic ablation we determined herein a range of behaviors, including anxiety and exploratory behavior in the elevated plus maze (EPM), associative learning in fear conditioning, and spatial learning and memory in the Morris water maze (MWM). We observed significant deficits in all tests, suggesting structural and/or functional alterations in brain regions such as the cortex, amygdala and the hippocampus. In agreement with these findings, immunohistochemistry revealed reduced numbers of γ amino butyric acid (GABA) GABAergic interneurons, but not of glutamatergic projection neurons, in the adult cerebral cortex. Reduced GABAergic interneurons were also observed in the amygdala, most notably in the basolateral nucleus. The paucity in GABAergic interneurons in adult Cend1−/− mice correlated with increased proliferation and apoptosis as well as reduced migration of neuronal progenitors from the embryonic medial ganglionic eminence (MGE), the origin of these cells. Further we noted reduced GABAergic neurons and aberrant neurogenesis in the adult dentate gyrus (DG) of the hippocampus, which has been previously shown to confer spatial learning and memory deficits. Our data highlight the necessity of Cend1 expression in the formation of a structurally and functionally normal brain phenotype

Enhancement of endogenous midbrain neurogenesis by microneurotrophin BNN-20 after neural progenitor grafting in a mouse model of nigral degeneration

We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the “weaver” mouse, a model of progressive nigrostriatal degeneration. Here, we extended our investigation in two clinically-relevant ways. First, we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors. Second, we assessed if BNN-20 can boost the outcome of mouse neural progenitor cell intranigral transplantations in weaver mice, at late stages of degeneration. We found that BNN-20 has limited direct effects on cultured human induced pluripotent stem cell-derived neural progenitor cells, marginally enhancing their differentiation towards neurons and partially reversing the pathological phenotype of dopaminergic neurons generated from parkinsonian donors. In agreement, we found no effects of BNN-20 on the mouse neural progenitor cells grafted in the substantia nigra of weaver mice. However, the graft strongly induced an endogenous neurogenic response throughout the midbrain, which was significantly enhanced by the administration of microneurotrophin BNN-20. Our results provide straightforward evidence of the existence of an endogenous midbrain neurogenic system that can be specifically strengthened by BNN-20. Interestingly, the lack of major similar activity on cultured human induced pluripotent stem cell-derived neural progenitors and their progeny reveals the in vivo specificity of the aforementioned pro-neurogenic effect

Involvement of proteasome activation

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by a progressive decline in a variety of cognitive and non-cognitive functions. The amyloid beta protein cascade hypothesis places the formation of amyloid beta protein aggregates on the first position in the complex pathological cascade leading to neurodegeneration, and therefore AD might be considered to be a protein-misfolding disease. The Ubiquitin Proteasome System (UPS), being the primary protein degradation mechanism with a fundamental role in the maintenance of proteostasis, has been identified as a putative therapeutic target to delay and/or to decelerate the progression of neurodegenerative disorders that are characterized by accumulated/aggregated proteins. The purpose of this study was to test if the activation of proteasome in vivo can alleviate AD pathology. Specifically by using two compounds with complementary modes of proteasome activation and documented antioxidant and redox regulating properties in the 5xFAD transgenic mice model of AD, we ameliorated a number of AD related deficits. Shortly after proteasome activation we detected significantly reduced amyloid-beta load correlated with improved motor functions, reduced anxiety and frailty level. Essentially, to our knowledge this is the first report to demonstrate a dual activation of the proteasome and its downstream effects. In conclusion, these findings open up new directions for future therapeutic potential of proteasome-mediated proteolysis enhancement.publishersversionpublishe

Long Non-coding RNAs Associated With Neurodegeneration-Linked Genes Are Reduced in Parkinson’s Disease Patients

Transcriptome analysis has identified a plethora of long non-coding RNAs (lncRNAs) expressed in the human brain and associated with neurological diseases. However, whether lncRNAs expression levels correlate with Parkinson’s disease (PD) pathogenesis remains unknown. Herein, we show that a number of lncRNA genes encompassing transcriptional units in close proximity to PD-linked protein-coding genes, including SNCA, LRRK2, PINK1, DJ-1, UCH-L1, MAPT and GBA1, are expressed in human dopaminergic cells and post-mortem material, such as cortex, Substantia Nigra and cerebellum. Interestingly, these lncRNAs are upregulated during neuronal differentiation of SH-SY5Y cells and of dopaminergic neurons generated from human fibroblast-derived induced pluripotent stem cells. Importantly, six lncRNAs are found under-expressed in the nigra and three in the cerebellum of PD patients compared to controls. Simultaneously, SNCA mRNA levels are increased in the nigra, while LRRK2 and PINK1 mRNA levels are decreased both in the nigra and the cerebellum of PD subjects compared to controls, indicating a possible correlation between the expression profile of the respective lncRNAs with their adjacent coding genes. Interestingly, all dysregulated lncRNAs are also detected in human peripheral blood mononuclear cells and four of them in exosomes derived from human cerebrospinal fluid, providing initial evidence for their potential use as diagnostic tools for PD. Our data raise the intriguing possibility that these lncRNAs may be involved in disease pathogenesis by regulating their neighboring PD-associated genes and may thus represent novel targets for the diagnosis and/or treatment of PD or related diseases

Prox1 Regulates the Notch1-Mediated Inhibition of Neurogenesis

During development of the spinal cord, Prox1 controls the balance between proliferation and differentiation of neural progenitor cells via suppression of Notch1 gene expression

Cend1, a Story with Many Tales: From Regulation of Cell Cycle Progression/Exit of Neural Stem Cells to Brain Structure and Function

Neural stem/precursor cells (NPCs) generate the large variety of neuronal phenotypes comprising the adult brain. The high diversity and complexity of this organ have its origin in embryonic life, during which NPCs undergo symmetric and asymmetric divisions and then exit the cell cycle and differentiate to acquire neuronal identities. During these processes, coordinated regulation of cell cycle progression/exit and differentiation is essential for generation of the appropriate number of neurons and formation of the correct structural and functional neuronal circuits in the adult brain. Cend1 is a neuronal lineage-specific modulator involved in synchronization of cell cycle exit and differentiation of neuronal precursors. It is expressed all along the neuronal lineage, from neural stem/progenitor cells to mature neurons, and is associated with the dynamics of neuron-generating divisions. Functional studies showed that Cend1 has a critical role during neurogenesis in promoting cell cycle exit and neuronal differentiation. Mechanistically, Cend1 acts via the p53-dependent/Cyclin D1/pRb signaling pathway as well as via a p53-independent route involving a tripartite interaction with RanBPM and Dyrk1B. Upon Cend1 function, Notch1 signaling is suppressed and proneural genes such as Mash1 and Neurogenins 1/2 are induced. Due to its neurogenic activity, Cend1 is a promising candidate therapeutic gene for brain repair, while the Cend1 minimal promoter is a valuable tool for neuron-specific gene delivery in the CNS. Mice with Cend1 genetic ablation display increased NPC proliferation, decreased migration, and higher levels of apoptosis during development. As a result, they show in the adult brain deficits in a range of motor and nonmotor behaviors arising from irregularities in cerebellar cortex lamination and impaired Purkinje cell differentiation as well as a paucity in GABAergic interneurons of the cerebral cortex, hippocampus, and amygdala. Taken together, these studies highlight the necessity for Cend1 expression in the formation of a structurally and functionally normal brain

Brain Infection by Group B Streptococcus Induces Inflammation and Affects Neurogenesis in the Adult Mouse Hippocampus

Central nervous system infections caused by pathogens crossing the blood–brain barrier are extremely damaging and trigger cellular alterations and neuroinflammation. Bacterial brain infection, in particular, is a major cause of hippocampal neuronal degeneration. Hippocampal neurogenesis, a continuous multistep process occurring throughout life in the adult brain, could compensate for such neuronal loss. However, the high rates of cognitive and other sequelae from bacterial meningitis/encephalitis suggest that endogenous repair mechanisms might be severely affected. In the current study, we used Group B Streptococcus (GBS) strain NEM316, to establish an adult mouse model of brain infection and determine its impact on adult neurogenesis. Experimental encephalitis elicited neurological deficits and death, induced inflammation, and affected neurogenesis in the dentate gyrus of the adult hippocampus by suppressing the proliferation of progenitor cells and the generation of newborn neurons. These effects were specifically associated with hippocampal neurogenesis while subventricular zone neurogenesis was not affected. Overall, our data provide new insights regarding the effect of GBS infection on adult brain neurogenesis