The major histocompatibility complex participates in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra and the aggregation of alpha-synuclein (α-syn). The central nervous system (CNS) has previously been considered as an immune-privileged area. However, studies have shown that the immune responses are involved in PD. The major histocompatibility complex (MHC) presents antigens from antigen-presenting cells (APCs) to T lymphocytes, immune responses will be induced. MHCs are expressed in microglia, astrocytes, and dopaminergic neurons. Single nucleotide polymorphisms in MHC are related to the risk of PD. The aggregated α-syn triggers the expression of MHCs by activating glia cells. CD4+ and CD8+ T lymphocytes responses and microglia activation are detected in brains of PD patients. In addiction immune responses further increase blood-brain barrier (BBB) permeability and T cell infiltration in PD. Thus, MHCs are involved in PD through participating in immune and inflammatory responses.

Thioredoxin-1 decreases alpha-synuclein induced by MPTP through promoting autophagy-lysosome pathway.

Parkinson's disease (PD) is characterized by the formation of Lewy body in dopaminergic neurons in the substantia nigra pars compacta (SNpc). Alpha-synuclein (α-syn) is a major component of Lewy body. Autophagy eliminates damaged organelles and abnormal aggregated proteins. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays roles in protecting dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the relationship between Trx-1 and α-syn in PD is still unknown. In the present study, the movement disorder and dopaminergic neurotoxicity in MPTP-treated mice were improved by Trx-1 overexpression and were aggravated by Trx-1 knockdown in the SNpc in mice. The expression of α-syn was increased in the SNpc of MPTP-treated mice, which was inhibited by Trx-1 overexpression and was exacerbated in Trx-1 knockdown mice. Autophagosomes was increased under electron microscope after MPTP treatment, which were recovered in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown in the SNpc in mice. The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase 1 (PINK1), Parkin, LC3 II and p62 were increased by MPTP, which were blocked in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown mice. Cathepsin D was decreased by MPTP, which was restored in Trx-1 overexpressing mice and was further decreased in Trx-1 knockdown mice. The mRFP-GFP-LC3 green fluorescent dots were increased by 1-methyl-4-phenylpyridinium (MPP+) and further increased in Trx-1 siRNA transfected PC12 cells, while mRFP-GFP-LC3 red fluorescent dots were increased in Trx-1 overexpressing cells. These results indicate that Trx-1 may eliminate α-syn in PD mice through potentiating autophagy-lysosome pathway.

Olfactory bulb neurogenesis depending on signaling in the subventricular zone.

Olfaction is a crucial sense that is essential for the well-being and survival of individuals. Olfactory bulb (OB) is the first olfactory relay station, and its function depends on newly generated neurons from the subventricular zone (SVZ). These newly born neurons constantly migrate through the rostral migratory stream to integrate into existing neural networks within the OB, thereby contributing to olfactory information processing. However, the mechanisms underlying the contribution of SVZ adult neurogenesis to OB neurogenesis remain largely elusive. Adult neurogenesis is a finely regulated multistep process involving the proliferation of adult neural stem cells (aNSCs) and neural precursor cells, as well as the migration and differentiation of neuroblasts, and integration of newly generated neurons into preexisting neuronal circuitries. Recently, extensive studies have explored the mechanism of SVZ and OB neurogenesis. This review focused on elucidating various molecules and signaling pathways associated with OB neurogenesis dependent on the SVZ function. A better understanding of the mechanisms underlying the OB neurogenesis on the adult brain is an attractive prospect to induce aNSCs in SVZ to generate new neurons to ameliorate olfactory dysfunction that is involved in various diseases. It will also contribute to developing new strategies for the human aNSCs-based therapies.

TRPV4 contributes to ER stress and inflammation: implications for Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Its molecular mechanism is still unclear, and pharmacological treatments are unsatisfactory. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective Ca2+ channel. It has recently emerged as a critical risk factor in the pathophysiology of neuronal injuries and cerebral diseases. Our previous study reported that TRPV4 contributed to endoplasmic reticulum (ER) stress in the MPP+-induced cell model of PD. In the present study, we detected the role and the mechanism of TRPV4 in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. METHODS: Intracerebral injection of an adeno-associated virus (AAV) into the substantia nigra (SN) of mice was used to knockdown or upregulate the expression of TRPV4 and intraperitoneal injection of MPTP. Rotarod and pole tests were used to evaluate the locomotor ability of mice. We used immunohistochemistry, Nissl staining and Western blot to detect the alterations in the number of tyrosine hydroxylase (TH)-positive neurons, Nissl-positive neurons, the levels of ER stress-associated molecules and proinflammatory cytokines in the SN. RESULTS: The SN was transfected with AAV for 3 weeks and expressed the target protein with green fluorescence. Knockdown of TRPV4 via injection of a constructed AAV-TRPV4 shRNAi into the SN alleviated the movement deficits of PD mice. Upregulation of TRPV4 via injection of a constructed AAV-TRPV4 aggravated the above movement disorders. The expression of TRPV4 was upregulated in the SN of MPTP-treated mice. Injection of AAV-TRPV4 shRNAi into the SN rescued the number of TH-positive and Nissl-positive neurons in the SN decreased by MPTP, while injection of AAV-TRPV4 induced the opposite effect. Moreover, MPTP-decreased Sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA2) and pro-cysteinyl aspartate specific proteinase-12 (procaspase-12), MPTP-increased Glucose-regulated protein 78 (GRP78), Glucose-regulated protein 94 (GRP94) and C/EBP homologous protein (CHOP) were inhibited by AAV-TRPV4 shRNAi infection, and enhanced by AAV-TRPV4. In the same way, MPTP-decreased procaspase-1, MPTP-increased Interleukin-18 (IL-18), Cyclooxgenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) were inhibited by AAV-TRPV4 shRNAi, or further exacerbated by AAV-TRPV4. CONCLUSIONS: These results suggest that TRPV4 mediates ER stress and inflammation pathways, contributing to the loss of dopamine (DA) neurons in the SN and movement deficits in PD mice. Moreover, this study provides a new perspective on molecular targets and gene therapies for the treatment of PD in the future.

Thioredoxin-1 Rescues MPP+/MPTP-Induced Ferroptosis by Increasing Glutathione Peroxidase 4.

Parkinson's disease (PD), a common neurodegenerative disease, is typically associated with the loss of dopaminergic neuron in the substantia nigra pars compacta (SNpc). Ferroptosis is a newly identified cell death, which associated with iron accumulation, glutathione (GSH) depletion, lipid peroxidation formation, reactive oxygen species (ROS) accumulation, and glutathione peroxidase 4 (GPX4) reduction. It has been reported that ferroptosis is linked with PD.Thioredoxin-1 (Trx-1) is a redox regulating protein and plays various roles in regulating the activity of transcription factors and inhibiting apoptosis. However, whether Trx-1 plays the role in regulating ferroptosis involved in PD is still unknown. Our present study showed that 1-methyl-4-phenylpyridinium (MPP+) decreased cell viability, GPX4, and Trx-1, which were reversed by Ferrostatin-1 (Fer-1) in PC 12 cells and SH-SY5Y cells. Moreover, the decreased GPX4 and GSH, and increased ROS were inhibited by Fer-1 and Trx-1 overexpression. We further repeated that behavior deficits resulted from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were improved in Trx-1 overexpression transgenic mice. Trx-1 reversed the decreases of GPX4 and tyrosine hydroxylase (TH) induced by MPTP in the substantia nigra pars compacta (SNpc). Our results suggest that Trx-1 inhibits ferroptosis in PD through regulating GPX4 and GSH.