Astrocyte dysfunction and inflammation are associated with the pathogenesis of major depressive disorder (MDD). However, the mechanisms underlying these effects remain largely unknown. Here, we found that multiple endocrine neoplasia type 1 (Men1; protein: menin) expression is attenuated in the brain of mice exposed to CUMS (chronic unpredictable mild stress) or lipopolysaccharide. Astrocyte-specific reduction of Men1 (GcKO) led to depressive-like behaviors in mice. We observed enhanced NF-κB activation and IL-1β production with menin deficiency in astrocytes, where depressive-like behaviors in GcKO mice were restored by NF-κB inhibitor or IL-1β receptor antagonist. Importantly, we identified a SNP, rs375804228, in human MEN1, where G503D substitution is associated with a higher risk of MDD onset. G503D substitution abolished menin-p65 interactions, thereby enhancing NF-κB activation and IL-1β production. Our results reveal a distinct astroglial role for menin in regulating neuroinflammation in depression, indicating that menin may be an attractive therapeutic target in MDD.

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BACKGROUND: Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer's disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were reexamined in search of candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. METHODS: Quantitative phosphoproteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays was used to investigate the associated regulatory signaling networks. Histological, electrochemical, and behavioral assays were performed in conditional knockout, small hairpin RNAmediated knockdown, and AD-related mice models to evaluate the relevance of CDK5 to synaptic homeostasis and functions. RESULTS: Among candidates with known implications in synaptic modulations, BAG3 ranked the highest. CDK5mediated phosphorylation on S297/S291 (mouse/human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such effects were reversed by ectopic BAG3 reexpression. CONCLUSIONS: Our results highlight that the neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.

Menin (MEN1) is a critical modulator of tissue development and maintenance. As such, MEN1 mutations are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin is abundantly expressed in the nervous system, little is known with regard to its function in the adult brain. Here, we demonstrate that neuron-specific deletion of Men1 (CcKO) affects dendritic branching and spine formation, resulting in defects in synaptic function, learning, and memory. Furthermore, we find that menin binds to the p35 promoter region to facilitate p35 transcription. As a primary Cdk5 activator, p35 is expressed mainly in neurons and is critical for brain development and synaptic plasticity. Restoration of p35 expression in the hippocampus and cortex of Men1 CcKO mice rescues synaptic and cognitive deficits associated with Men1 deletion. These results reveal a critical role for menin in synaptic and cognitive function by modulating the p35-Cdk5 pathway.

Astrocytes are the greatest number and special ramified cell-type in CNS. They have several functions: their processes and cerebral vessels form the blood-brain barrier (BBB); their synapses represent the third element of the tripartite synapse; they provide a certain degree of metabolic supplement for neurons.Astrocytes provide essential metabolic support for neighboring neurons and other cell types, and protect their neighboring cells by ingesting excessive glutamate and K + and releasing growth

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and psychiatric problems. Recent studies demonstrated that transplantation of all kinds of human stem cells into patients with PD could help replacing endogenous degenerating dopamine (DA) neurons and ameliorate the clinical symptoms of PD (2, 6, 7).Recent studies have revealed the successful reversal of parkinsonian symptoms in monkeys, rats, and patients with PD after transplantation of different kinds of stem cells (18,22,23,24). However, the safety and valuation of transplantation of neural precursor cells (NPCs) remains controversial.A boy with ataxia telangiectasia (AT) was treated not only with intracerebellar but intrathecal injection of human fetal NPCs. Four years after the transplantation he came with a multifocal brain tumor. Molecular and cytogenetic genetics detectionsParkinson's disease (PD), also called parkinsonism, is the most common central nervous system degenerative disease secondary to dopaminergic neuron loss in the substantia nigra pars compacta (SNc), decrease in the synthesis of dopamine and excitation of acetylcholine (24). Most evident symptoms are movement-related, including movement disorders, tremor and rigidity.Gradually, thinking and behavioral problems may arise, with dementia commonly occurring in the last phases of the disease, whereas depression is the most common psychiatric symptom.Dementia and depression will heavily influence the quality of patient lives. Other symptoms include sensory, emotional AIM: The aim of this study was to evaluate the clinical safety, feasibility and efficacy of transplantation of neural precursor cells (NPCs) in the treatment for Parkinson's disease (PD). MATERIAL and METHODS:Twenty-one patients, aged 42-79 years (median age 57.33 years), participated in the study. A total of 3 × 107 NPCs in 0.25 ml were deposited unilaterally into the striatum. To access the effectiveness of first transplantation surgery, comparisons between the resulting pre-first surgery evaluation and pre-second surgery evaluation were made with repeatedmeasures analysis of variance. Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn-Yahr, PDQ-39 and Schwab-England Scores were used to evaluate the Parkinson patients' neurofunctions. Four aspects were used to assess the possible side effects of transplantation: a) tumor formation, b) immune rejection and use of immunosuppressant, c) graft induced complication and d) delivery related side effects. RESULTS:This study demonstrated that the symptoms of PD patients were statistically improved after transplantation (P<0.01). There were no obvious side effects of transplantation. CONCLUSION:Transplantation of neural precursor cells may be a valid and safe treatment method for Parkinson's Disease.

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