Hainan Zhang

Mutation analysis of Parkin , PINK1 and DJ - 1 genes in Chinese patients with sporadic early onset parkinsonism

Early onset parkinsonism (EOP) has been associated with mutations in the Parkin, PINK1, and DJ-1 genes. We studied the prevalence of mutations in all three genes in 127 unrelated Chinese patients with apparently sporadic EOP using direct sequencing analysis and real-time quantitative PCR analysis assay. There are 16 patients (12.6%) with mutations of Parkin gene, four patients (3.1%) with mutations of PINK1 gene, and three patients (2.4%) with mutation of DJ-1 gene. In conclusion, Parkin gene mutation is the most common pathogenic factor in Chinese patients with sporadic EOP. Mutations of DJ-1 and PINK1 gene are also found in Chinese patients with sporadic EOP.

Lower serum UA levels in Parkinson's disease patients in the Chinese population

Parkinsons disease (PD) is the second most common neurodegenerative disease in the world, and oxidative stress plays an important role in its pathogenesis. Uric acid (UA) is a product of purine metabolism and is a natural antioxidant that can relieve the oxidative stress that occurs in PD. Recent studies have indicated that the serum UA level are associated with a risk of PD and PD progression of motor symptoms and have proposed UA as a possible biomarker of the underlying pathophysiology of PD. In our study, we investigated the association between serum UA level and PD in a Chinese population. We found that the serum UA levels in PD patients were lower than the levels in control patients and were correlated with PD progression and duration in the Chinese population. These associations were observed in both genders, but hyperuricemia is more strongly associated with lower rates of PD among men compared to women and older people compared to younger people. Our results indicate that UA could be an important biomarker of PD and that the serum UA level could be a useful biomarker of PD diagnosis and disease progression.

Genetic variations of Omi/HTRA2 in Chinese patients with Parkinson's disease.

Parkinsons disease (PD) is the second most common neurodegenerative disorder, with approximately 5-10% of PD cases being linked to genetic factors. The Htra serine peptidase 2 (HTRA2) gene, also known as Omi, was found to be associated with PD in a cohort of German PD patients. However, subsequent studies have indicated that some variants of Omi/HTRA2 may not be related to PD. In order to investigate whether the Omi/HTRA2 gene is related to PD in Han Chinese PD patients, molecular analysis for the Omi/HTRA2 gene was performed in 404 Chinese PD patients and 504 normal individuals. Our present study revealed 2 novel variations. The IVS5+29T>A variant may be a risk factor for PD (P<0.05), while the c.G77A variant might be a pathogenic mutation. However, the findings need to be validated in a larger population using further functional studies.

Idiopathic hypertrophic spinal pachymeningitis: a case report and review of literature

PurposeTo report an unusual case of idiopathic hypertrophic spinal pachymeningitis (IHSP) with a review of relevant literature and to discuss the etiology, clinical features, imaging, treatment and prognosis of IHSP.MethodsThe case of a 44-year-old woman is reported. MEDLINE was used to search relevant literatures written in English since 2004.ResultsThe patient suffered from progressive mild thoracic backache followed by truncal and lower extremity weakness, numbness and urinary retention. The diagnosis was confirmed by magnetic resonance (MR) imaging and histopathologic examination. Although she received corticosteroid therapy and decompressive surgery, the patient suffered a rapid relapse probably because of the withdrawal of postoperative steroid therapy.ConclusionsIHSP is a rare disease characterized by inflammatory hypertrophy of the dura mater without identifiable cause and featured clinical progress of radiculalgia to myelopathy. It is a diagnosis of exclusion. In our view, surgical decompression with postoperative steroid therapy may be optimal. Furthermore,we speculated that increased levels of protein and cell count in cerebrospinal fluid (CSF) might be positively related to the disease progression. High inflammatory signs or CSF protein and cell levels before surgery or postoperative residual lesions are possible reasons of poor prognosis in patients with IHSP.

Stroke-like Migraine Attacks after Radiation Therapy Syndrome.

Objective: To summarize the clinical presentation, pathogenesis, neuroimaging, treatment, and outcome of stroke-like migraine attacks after radiation therapy (SMART) syndrome, and to propose diagnostic criteria for this disorder. Data Sources: We searched the PubMed database for articles in English published from 1995 to 2015 using the terms of “stroke-like AND migraine AND radiation.” Reference lists of the identified articles and reviews were used to retrieve additional articles. Study Selection: Data and articles related to late-onset effects of cerebral radiation were selected and reviewed. Results: SMART is a rare condition that involves complex migraines with focal neurologic deficits following cranial irradiation for central nervous system malignancies. The recovery, which ranges from hours to days to weeks, can be partial or complete. We propose the following diagnostic criteria for SMART: (1) Remote history of therapeutic external beam cranial irradiation for malignancy; (2) prolonged, reversible clinical manifestations mostly years after irradiation, which may include migraine, seizures, hemiparesis, hemisensory deficits, visuospatial defect, aphasia, confusion and so on; (3) reversible, transient, unilateral cortical gadolinium enhancement correlative abnormal T2 and fluid-attenuated inversion recovery signal of the affected cerebral region; (4) eventual complete or partial recovery, the length of duration of recovery ranging from hours to days to weeks; (5) no evidence of residual or recurrent tumor; (6) not attributable to another disease. To date, no specific treatment has been identified for this syndrome. Conclusions: SMART is an extremely rare delayed complication of brain irradiation. However, improvements in cancer survival rates have resulted in a rise in its frequency. Hence, awareness and recognition of the syndrome is important to make a rapid diagnosis and avoid aggressive interventions such as brain biopsy and cerebral angiography.

Hsp70 participates in PINK1-mediated mitophagy by regulating the stability of PINK1

INTRODUCTION Loss-of function mutations in PTEN-induced putative kinase 1 (PINK1) is one of the most common causes of autosomal recessive Parkinsons disease (PD). PINK1-mediated mitophagy is critical to mitochondrial quality control and plays an important role in PD pathogenesis. Therefore, identifying the regulatory mechanisms of PINK1 expression may provide novel opportunities for PD therapy. Heat-shock protein 70kDa (Hsp70) is involved in neuroprotection as a molecular chaperone in neurodegenerative disorders such as PD. Thus far, the interaction between Hsp70 and PINK1 remains unclear. OBJECTIVES This study aimed to verify the interaction between Hsp70 and PINK1, as well as the role of Hsp70 in PINK1 stability, cell autophagy, and PINK1-mediated mitophagy. METHODS The interaction and subcellular location of Hsp70 and PINK1 were verified by coimmunoprecipitation and immunofluorescence colocalization. Western blot analysis was used to determine the role of Hsp70 in PINK1 stability. Immunofluorescence and Western blot analyses were performed to determine the role of Hsp70 in PINK1-mediated mitophagy. RESULTS We identified the interaction between Hsp70 and PINK1 and revealed that Hsp70 stabilized PINK1 by decreasing PINK1 degradation. Our data demonstrated that Hsp70 participated in PINK1-mediated mitophagy. CONCLUSIONS Hsp70participated in PINK1-mediated mitophagy by stabilizing PINK1.

Prediction of orthostatic hypotension in multiple system atrophy and Parkinson disease

Orthostatic hypotension (OH) is common in multiple system atrophy (MSA) and Parkinson disease (PD), generally assessed through a lying-to-standing orthostatic test. However, standing blood pressure may not be available due to orthostatic intolerance or immobilization for such patients. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were successively measured in supine, sitting, and standing positions in patients with MSA and PD. Receiver operating characteristic analysis was used to evaluate diagnostic performance of the drops of sitting SBP or DBP. OH and severe OH were respectively regarded as “gold standard”. The drops of SBP in standing position were associated with increased disease severity for MSA and correlated with age for PD. In MSA group, drops in sitting SBP ≥ 14 mmHg or DBP ≥ 6 mmHg had highest validity for prediction of OH, and drops in sitting SBP ≥ 18 mmHg or DBP ≥ 8 mmHg for severe OH. In PD group, drops in sitting SBP ≥ 10 mmHg or DBP ≥ 6 mmHg had highest validity for prediction of OH. The lying-to-sitting orthostatic test is an alternative method for detection of OH in MSA and PD, especially when standing BP could not be validly measured due to various reasons.

BAG2 structure, function and involvement in disease

Bcl2-associated athanogene 2 (BAG2) shares a similar molecular structure and function with other BAG family members. Functioning as a co-chaperone, it interacts with the ATPase domain of the heat shock protein 70 (dHsp70) through its BAG domain. It also interacts with many other molecules and regulates various cellular functions. An increasing number of studies have indicated that BAG2 is involved in the pathogenesis of various diseases, including cancers and neurodegenerative diseases. This paper is a comprehensive review of the structure, functions, and protein interactions of BAG2. We also discuss its roles in diseases, including cancer, Alzheimer’s disease, Parkinson’s disease and spinocerebellar ataxia type-3. Further research on BAG2 could lead to an understanding of the pathogenesis of these disorders or even to novel therapeutic approaches.

Mutation analysis of PINK1 gene in patients with early-onset Parkinsonism.

OBJECTIVE To determine the frequency of mutations in PINK1 in Chinese Han people with sporadic early-onset Parkinsonism (EOP). METHODS DNA sequencing was used to detect point mutations and small deletions/insertions, and quantitative real-time PCR was carried out to detect deletions/insertions and rearrangements in 149 patients and 150 healthy controls. RESULTS Four heterozygous mutations in PINK1 were identified, including 3 missense mutations (c.832C>G, c. 938C>T, c.1 220G>A) and ex 3-8 del. A novel single nucleotide polymorphism (SNP) c.899+18G>A and 14 reported SNPs were identified. Chi-square test showed that c.189C> T and c.960-5G>A had significant difference in the genotype frequencies and allele frequencies between the patients and the controls (for c.189C>T genotype χ(2)=21.244,P<0.0001; T allele χ(2)=24.353,P<0.0001, and for c.960-5G>A genotypes χ(2)=6.524,P =0.038; A allele χ(2)=6.725,P=0.0095). CONCLUSION About 3.35% Chinese Han patients with EOP carry mutations in PINK1. Two SNPs c.189C>T and c.960-5G>A may contribute to the risk of EOP in Chinese Han people.

BAG5 Interacts with DJ-1 and Inhibits the Neuroprotective Effects of DJ-1 to Combat Mitochondrial Oxidative Damage

Loss-of-function mutations in gene encoding DJ-1 contribute to the pathogenesis of autosomal recessive early-onset familial forms of Parkinsons disease (PD). DJ-1 is a multifunctional protein and plays a protective role against oxidative stress-induced mitochondrial damage and cell death, but the exact mechanism underlying this is not yet clearly understood. Here, using coimmunoprecipitation (Co-IP) and immunofluorescence methods, we prove that Bcl-2-associated athanogene 5 (BAG5), a BAG family member, interacts with DJ-1 in mammalian cells. Moreover, we show that BAG5 could decrease stability of DJ-1 and weaken its role in mitochondrial protection probably by influencing dimerization in stress condition. Our study reveals the relationship of BAG5 and DJ-1 suggesting a potential role for BAG5 in the pathogenesis of PD through its functional interactions with DJ-1.