Person:

Lin, Zhicheng

A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research.

Background: Autophagy-mediated self-digestion of cytoplasmic inclusions may be protective against neurodegenerative diseases such as Parkinson’s disease (PD). However, excessive autophagic activation evokes autophagic programmed cell death. Methods: In this study, we aimed at exploring the role of autophagy in the pathogenesis of rotenone-induced cellular and animal models for PD. Results: Reactive oxygen species over-generation, mitochondrial membrane potential reduction or apoptosis rate elevation occurred in a dose-dependent fashion in rotenone-treated human neuroblastoma cell line SH-SY5Y. The time- and dose-dependent increases in autophagic marker microtubule-associated protein1 light chain 3 (LC3) expression and decreases in autophagic adaptor protein P62 were observed in this cellular model. LC3-positive autophagic vacuoles were colocalized with alpha-synuclein-overexpressed aggregations. Moreover, the number of autophagic vacuoles was increased in rotenone-based PD models in vitro and in vivo. Conclusions: These data, along with our previous finding showing rotenone-induced toxicity was prevented by the autophagy enhancers and was aggravated by the autophagy inhibitors in SH-SY5Y, suggest that autophagy contributes to the pathogenesis of PD, attenuates the rotenone toxicity and possibly represents a new subcellular target for treating PD.

Background: Cerebral venous sinus thrombosis (CVST) is a relatively rare cerebrovascular condition which accounts for 0.5% of all strokes. Risk of CVST has been documented in patients with numerous conditions including central nervous system infections, however, Japanese encephalitis (JE, epidemic encephalitis type B) with CVST has not been reported previously. Case Presentation: Here, we present a case of JE with CVST in a 17-year-old man. On admission, the patient was initially diagnosed as intracranial infection, and soon after, brain magnetic resonance (MR) imaging (MRI) and MR Venography (MRV) confirmed the diagnosis of CVST. Moreover, the blood JE-specific IgM antibody which proved weakly positive at first, turned positive one week later. Consequently, our patient was diagnosed as CVST accompanied by JE. Anticoagulant and anti-infective therapy were initiated, which eventually lead to gradual recovery of the patient. Conclusions: To our knowledge, this is the first case report of CVST associated with JE. MRI and MRV represent a prime method for the diagnosis of CVST, while the positivity of JE virus IgM antibody, especially increased antibody levels within a short period, is of great significance to diagnose JE. The early diagnosis and timely treatment of this potentially lethal condition would improve its prognosis significantly.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome characterized by hyperkinetic movements, seizures, cognitive impairment, neuropsychiatric symptoms, elevated serum biochemical indicators and acanthocytes detection in peripheral blood smear. Vacuolar protein sorting 13A (VPS13A) gene mutations have been proven to be genetically responsible for the pathogenesis of ChAc. Herein, based on the typical clinical symptoms and neuroimaging features, we present two suspected ChAc cases which are further genetically confirmed by four novel VPS13A gene mutations. Nevertheless, the sharp contrast between the population base and published ChAc reports implies that ChAc is considerably underdiagnosed in China. Therefore, we conclude several suggestive features and propose a diagnostic path of ChAc from a clinical, genetic and neuroimaging perspective, aiming to facilitate the diagnosis and management of ChAc in China.

Background: Accumulating evidence has demonstrated that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a part of Lewy body inclusions and involves the pathogenesis of Parkinson’s disease (PD). However, it remains unknown whether or not genetic variation at the GAPDH locus contributes to the risk for PD. Methods: A total of 302 sporadic PD patients and 377 control subjects were recruited in our study for assessing two single nucleotide polymorphisms (rs3741918 and rs1060619) in the GAPDH gene. Both allelic association and additive models were used to analyze association between GAPDH variants and risk for PD. Results: Both polymorphisms were significantly associated with risk for PD after correction by Bonferroni multiple testing. The minor allele of rs3741918 was associated with decreased risk of sporadic PD (allelic contrast, OR = 0.74, 95% CI: 0.59–0.93, corrected P = 0.028; additive model, OR = 0.73, 95% CI: 0.58–0.92, corrected P = 0.018). While for the rs1060619 locus, the minor allele conferred increased risk for PD (allelic contrast, OR = 1.41, 95% CI: 1.14–1.75, corrected P = 0.007; additive model, OR = 1.43, 95% CI: 1.15–1.79, corrected P = 0.002). Conclusion: Our study indicates that GAPDH variants confer susceptibility to sporadic PD in a Chinese Han population, which is consistent with the role of GAPDH protein in neuronal apoptosis. To our knowledge, this is the first study of genetic association between GAPDH locus and risk for PD in the Chinese population.

GABA neurons, born in remote germinative zones in the ventral forebrain (telencephalon), migrate tangentially in two spatially distinct streams to adopt their specific positions in the developing cortex. The cell types and molecular cues that regulate this divided migratory route remains to be elucidated. Here we show that embryonic vascular networks are strategically positioned to fulfill the task of providing support as well as critical guidance cues that regulate the divided migratory routes of GABA neurons in the telencephalon. Interestingly, endothelial cells of the telencephalon are not homogeneous in their gene expression profiles. Endothelial cells of the periventricular vascular network have molecular identities distinct from those of the pial network. Our data suggest that periventricular endothelial cells have intrinsic programs that can significantly mold neuronal development and uncovers new insights into concepts and mechanisms of CNS angiogenesis from both developmental and disease perspectives.

Background: Mutations of the glucocerebrosidase (GBA) gene have reportedly been associated with Parkinson disease (PD) in various ethnic populations such as Singaporean, Japanese, Formosan, Canadian, American, Portuguese, Greek, Brazilian, British, Italian, Ashkenazi Jewish, southern and southwestern Chinese. The purpose of this study is to determine in central China whether or not the reported GBA mutations remain associated with PD. Methods: In this project, we conducted a controlled study in a cohort of 208 central Chinese PD patients and 298 controls for three known GBA mutations (L444P, N370S and R120W). Results: Our data reveals a significantly higher frequency of L444P mutation in GBA gene of PD cases (3.4%) compared with the controls (0.3%) (P = 0.007, OR = 10.34, 95% CI = 1.26 - 84.71). Specifically, the frequency of L444P mutation was higher in the late onset PD (LOPD) cases compared with that in control subjects. The N370S and R120W mutations were detected in neither the PD group nor the control subjects. Conclusions: Our observations demonstrated that the GBA L444P mutation confers genetic risk for PD, especially LOPD, among the population in the central China area.

Background: Microtubule-associated protein tau (MAPT) is a neuronal protein involved in the pathogenesis of several neurodegenerative diseases including Parkinson’s Disease (PD). Glycogen synthase kinase 3 beta (GSK3B) catalyzes phosphorylation in multiple sites of tau protein. However, whether or not there is any association between the GSK3B gene alteration, MAPT haplotype and PD remains unexplored in Chinese population, especially in central Chinese population. Results: Here, we aimed at studying the effect of MAPT rs242562 and GSK3B rs334558 on the risk of PD by performing a case-control association study in central China. Our data showed that all PD patients and controls were of MAPT H1/H1 diplotype in our study, thus confirming that the distribution of the MAPT H1 haplotype is common in China. GG genotype of MAPT rs242562 serves protection effect on PD risk in central Chinese population, while genotype of GSK3B rs334558 showed no difference between PD patients and controls. Conclusions: We conclude that the MAPT rs242562 is associated with PD in central China in the background of MAPT H1/H1 diplotype. The GG genotype of rs242562 displays protection against PD in subgroup with GSK3B rs334558 T carrier.

Parkinson’s disease (PD), a progressive neurodegenerative disorder, is characterized by irreversible dopaminergic neuron loss and intra-neuronal α-synuclein aggregation. High mobility group box 1 (HMGB1) has been proven to be involved in autophagy dysfunction induced by α-synuclein accumulation, and the Beclin1-vacuolar protein sorting 34 (Vps34) complex is of great importance to the initiation of autophagy. Nevertheless, the concrete interaction mechanism between HMGB1, α-synuclein and autophagy remains elusive, especially in the context of PD. Here in this study, we investigated the interaction between HMGB1 and α-synuclein in rotenone-induced PD cell models and their roles in autophagy flux. Results revealed elevated expression and cytosolic translocation of endogenous HMGB1 upon rotenone exposure. Besides, HMGB1 was found to be able to co-localize and interact with α-synuclein. Moreover, it had also been proven that HMGB1 could aggravate α-synuclein aggregation induced autophagy dysfunction via perturbing Beclin1-Vps34 complex formation. Based on these findings, we propose that HMGB1 is involved in rotenone-induced dopaminergic cell death via interacting with α-synuclein, perturbing the autophagy process, aggravating protein aggregation and finally propelling dopaminergic neurons to move from morbidity to mortality.

Altered activity of the human dopamine transporter gene (hDAT) is asssociated with several common and severe brain disorders including cocaine abuse. However, there is little a priori information on whether such alteration was due to nature (genetic variantion) or nurture (human behaviors such as cocaine abuse). This study investigated the correlation between seven markers throughout hDAT and its mRNA levels in postmortem ventral midbrain tissues from 18 cocaine abusers and 18 strictly matched drug-free controls in the African American population. Here we show that one major haplotype with same frequency in cocaine abusers versus drug-free controls displays a 37.1%-reduction of expression levels in cocaine abusers, compared to matched controls (P = 0.0057). The most studied genetic marker, variable number tandem repeats (VNTR) located in Exon 15 (3′VNTR), is not correlated with hDAT mRNA levels. A 5′ upstream VNTR (rs70957367) has repeat numbers positively correlated with expression levels in controls (r2 0.9536, P = 0.0235) but this positive correlation disappears in cocaine abusers. The findings suggest that varying hDAT activity is attributed to both genetics and cocaine abuse.