Background: Parkinson's disease (PD) is one of the neurodegeneration diseases characterized by the gradual loss of dopaminergic (DA) neurons in the substantia nigra region of the brain. Substantial evidence indicates that at the cellular level mitochondrial dysfunction is a key factor leading to pathological features such as neuronal death and accumulation of misfolded α-synuclein aggregations. Autologous transplantation of healthy purified mitochondria has shown to attenuate phenotypes in vitro and in vivo models of PD. However, there are significant technical difficulties in obtaining large amounts of purified mitochondria with normal function. In addition, the half-life of mitochondria varies between days to a few weeks. Thus, identifying a continuous source of healthy mitochondria via intercellular mitochondrial transfer is an attractive option for therapeutic purposes. In this study, we asked whether iPSCs derived astrocytes can serve as a donor to provide functional mitochondria and rescue injured DA neurons after rotenone exposure in an in vitro model of PD. Methods: We generated DA neurons and astrocytes from human iPSCs and hESCs. We established an astroglialneuronal co-culture system to investigate the intercellular mitochondrial transfer, as well as the neuroprotective effect of mitochondrial transfer. We employed immunocytochemistry and FACS analysis to track mitochondria.

Alzheimer’s disease (AD) is a neurodegenerative disease that currently cannot be cured by any drug or intervention, due to its complicated pathogenesis. Current animal and cellular models of AD are unable to meet research needs for AD. However, recent three-dimensional (3D) cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD. In this review, we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models, and propose possible solutions, in order to improve their application in AD research. Ethical concerns associated with human cerebral organoids are also discussed. We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.

Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. We found in this network that LK6, a serine/threonine protein kinase, plays a key role in promoting α-synuclein Ser129 phosphorylation by identification of LK6 knockout and overexpression. In vivo test was further confirmed that LK6 indeed enhances α-synuclein phosphorylation, accelerates the death of dopaminergic neurons, reduces the climbing ability and shortens the the life span of drosophila. Further, MAP kinase-interacting kinase 2a (Mnk2a), a human homolog of LK6, also been shown to make α-synuclein phosphorylation and leads to α-synuclein inclusion formation. On the mechanism, the phosphorylation mediated by LK6 and Mnk2a is controlled through ERK signal pathway by phorbolmyristate acetate (PMA) avtivation and PD98059 inhibition. Our findings establish pivotal role of Lk6 and Mnk2a in unprecedented signalling networks, may lead to new therapies preventing α-synuclein inclusion formation and neurodegeneration.

A stroke is a severe life-threatening disease with high fatality and disability rate. This investigation aimed to study the effect of Xiaoyao-jieyu-san (XYJY) on post-stroke depression (PSD) and its potential mechanisms. PSD rats were prepared using middle cerebral artery embolization (MCAO) and chronic unpredictable mild stress (CUMS), and divided into six groups (n = 10)-sham; MCAO; MCAO + CUMS (PSD); PSD + fluoxetine (1.84 mg/kg/day, 4 weeks); and PSD + XYJY (450 mg/kg/day and 900 mg/kg/day, 4 weeks). Body weight recording, despair swimming test, and sucrose preference test were performed at 0, 3 and 7 weeks. Histopathological examination and levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE) and brain-derived neurotrophic factor (BDNF) in ventral tegmental area-nucleus accumbens (VTA-NAc) tissue were determined at the end of a 7-week period. Real-time polymerase chain reaction PCR was used to determine mRNA expression of 5-HTR and 5-HTR, and Western blot was performed to determine expression of BDNF, corticotrophin-releasing factor (CRF), and cannabinoid receptors (CBR and CBR) in VTA-NAc tissue. High-performance liquid chromatography coupled with electrospray mass spectroscopy revealed that the constituents of XYJY are mainly paeoniflorin, imperatorin, naringin, arnesene, 2,3,5,4'-tetrahydroxyl-diphenylethylene-2-O-glucoside, kaempferol-3-O-rutinoside, quercetin, hesperidin, cycloastragenol and atractylenolide III. XYJY (900 mg/kg) increased the body weight of PSD rats, while XYJY (450 mg/kg and 900 mg/kg) shortened the duration of immobility and enhanced the sucrose preference of PSD rats. XYJY (450 mg/kg and 900 mg/kg) increased the levels of 5-HT, NE and BNDF, up-regulated mRNA expression of 5-HTR, down-regulated 5-HTR, and up-regulated BNDF, CBR, and CBR expression in the VTA-NAc tissue of PSD rats but down-regulated CRF. Collectively, the present findings suggested that XYJY has an ameliorative effect on PSD in rats via modulation of BNDF, cannabinoid receptors and CRF in VTA-NAc tissue.