During the development, tight regulation of the expansion of neural progenitor cells (NPCs) and their differentiation into neurons is crucial for normal cortical formation and function. In this study, we demonstrate that microRNA (miR)-128 regulates the proliferation and differentiation of NPCs by repressing pericentriolar material 1 (PCM1). Specifically, overexpression of miR-128 reduced NPC proliferation but promoted NPC differentiation into neurons both in vivo and in vitro. In contrast, the reduction of endogenous miR-128 elicited the opposite effects. Overexpression of miR-128 suppressed the translation of PCM1, and knockdown of endogenous PCM1 phenocopied the observed effects of miR-128 overexpression. Furthermore, concomitant overexpression of PCM1 and miR-128 in NPCs rescued the phenotype associated with miR-128 overexpression, enhancing neurogenesis but inhibiting proliferation, both in vitro and in utero. Taken together, these results demonstrate a novel mechanism by which miR-128 regulates the proliferation and differentiation of NPCs in the developing neocortex.DOI: http://dx.doi.org/10.7554/eLife.11324.001

Mutations in , which encodes leucine-rich repeat kinase 2, are the most common genetic cause of familial and sporadic Parkinson's disease (PD), a degenerative disease of the central nervous system that causes impaired motor function and, in advanced stages, dementia. Dementia is a common symptom of another neurodegenerative disease, Alzheimer's disease, and research suggests that there may be pathophysiological and genetic links between the two diseases. Aggregates of β amyloid [a protein produced through cleavage of amyloid precursor protein (APP)] are seen in both diseases and in PD patients carrying G2019S-mutant LRRK2. Using patient-derived cells, brain tissue, and PD model mice, we found that LRRK2 interacted with and phosphorylated APP at Thr within its intracellular domain (AICD). Phosphorylation of APP at Thr promoted AICD transcriptional activity and correlated with increased nuclear abundance of AICD and decreased abundance of a dopaminergic neuron marker in cultures and brain tissue. The AICD regulates the transcription of genes involved in cytoskeletal dynamics and apoptosis. Overexpression of AICD, but not a phosphodeficient mutant (AICD), increased the loss of dopaminergic neurons in older mice expressing LRRK2 Moreover, the amount of Thr-phosphorylated APP was substantially greater in postmortem brain tissue and dopaminergic neurons (generated by reprogramming skin cells) from LRRK2 patients than in those from healthy individuals. LRRK2 inhibitors reduced the phosphorylation of APP at Thr in the patient-derived dopaminergic neurons and in the midbrains of LRRK2 mice. Thus, APP is a substrate of LRRK2, and its phosphorylation promotes AICD function and neurotoxicity in PD.

Background: Exosomes are nano-sized extracellular vesicles secreted by most cell types and abundantly present in body fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes can spread toxic amyloid-beta (Aβ) and hyperphosphorylated tau between cells, contributing to neuronal loss in Alzheimer's disease (AD). Objective: To explore changes in the morphology, number, and pathological protein levels of urinary exosomes in AD patients compared with age-matched healthy subjects. Methods: In this study, enzyme-linked immunosorbent assay was used to detect the levels of Aβ1-42 and P-S396-tau (normalized by CD63) in urinary exosomes of AD patients and matched healthy subjects. We used transmission electron microscopy and nanoparticle tracking analysis to observe the exosomes. Results: We found that the levels of Aβ1-42 and P-S396-tau in the urinary exosomes of AD patients were higher than those of matched healthy controls. Exosomes taken from AD patients were more numerous. Conclusion: The differences in levels of Aβ1-42 and P-S396-tau and the quantity of urinary exosomes between AD patients and healthy controls may provide a basis for early diagnosis of AD.

Tumor in situ fluid (TISF) refers to the fluid at the local surgical cavity. We evaluated the feasibility of TISF-derived circulating tumor DNA (ctDNA) characterizing the genomic landscape for glioma. This retrospective study included TISF and tumor samples from 10 patients with glioma, we extracted cell-free DNA (cfDNA) from the TISF and then performed deep sequencing on that. And we compared genomic alterations between TISF and tumor tissue. Results showed that the concentration of cfDNA fragments from the patients for TISF ranged from 7.2 to 1,397 ng/ml. At least one tumor-specific mutation was identified in all 10 patients (100%). Further analysis of TISF ctDNA revealed a broad spectrum of genetic mutations, which have been reported to have clinical relevance. The analysis of concordance between TISF and tumor tissue reflected the spatiotemporal heterogeneity of glioma. Collectively, TISF ctDNA was a powerfully potential source for characterizing the genomic landscape of glioma, which provided new possibilities for precision medicine in patients with glioma.