Chun-yu Wang

Novel mutations of the SPG11 gene in hereditary spastic paraplegia with thin corpus callosum

BACKGROUND Hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is a clinically and genetically heterogeneous neurodegenerative disorder with genetic linkage to multi-loci. Recently pathogenic mutations in the KIAA1840 (now named SPG11) for SPG11, the major HSP-TCC locus, were identified; at least 42 different mutations have been detected. OBJECTIVE To study the clinical features and identify the SPG11 gene mutations in Chinese patients with HSP-TCC. METHODS Three kindreds with an autosomal recessive HSP-TCC and 5 cases with sporadic HSP-TCC in Chinese Hans were recruited. Detailed clinical history, neurological examination, MRI, electromyography, Mini Mental State Examination (MMSE), Spastic Paraplegia Rating Scale (SPRS) were presented. DNA samples of the 8 families were collected and mutation analysis of SPG11 gene was carried out by direct DNA sequencing. RESULTS Except for one patient whose age at onset was 3 years old, 10 patients manifested a relatively similar combination of adolescence-onset cognitive decline and spastic paraparesis with TCC on brain MRI. We identified 10 novel and one known mutations in our 8 HSP-TCC families, which were two nonsense mutations (c.5977C>T/p.Q1993X, c.4668T>A/p.Y1556X), three small deletions (c.6898_6899delCT/p.L2300AfsX2338, c.3719_3720delTA/p.I1240VfsX263, c.733_734delAT/p.M245VfsX246), four small insertions (c.7088_7089insATTA/p.Y2363X, c.2163_2164insT/p.I722YfsX731, c.7101_7102insT/p.K2368X, c.6790_6791insC/p.L2264PfsX2339), one deletion/insertion (c.654_655delinsG/p.S218RfsX219), and one splice mutation (c.7151+4_7151+7delAGTA/p.K2384fsX2386). Each family has a different mutation and all the mutations are predicted to cause early protein truncation. CONCLUSION This study widens the mutation spectrum of the SPG11 gene and the mutations in the SPG11 gene are also the major causative gene for HSP-TCC in the Chinese Hans. Screening of the whole gene is recommended in clinical practice.

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.

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.

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.

α‑synuclein induces apoptosis of astrocytes by causing dysfunction of the endoplasmic reticulum‑Golgi compartment

Although previous work has demonstrated that the overexpression of wild-type or mutant α-synuclein (α-syn) can induce cell death via a number of different mechanisms, including oxidative stress, dysfunction of the ubiquitin-proteasome degradation system, mitochondrial damage and endoplasmic reticulum (ER) stress, research interest has primarily focused on neurons. However, there is accumulating evidence that suggests that astrocytes may be involved in the earliest changes, as well as the progression of Parkinsons disease (PD), though the role of α-syn in astrocytes has not been widely studied. In the present study, it was revealed that the mutant α-syn (A53T and A30P) in astrocytes triggered ER stress via the protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2α signaling pathway. Astrocyte apoptosis was induced through a CCAAT-enhancer-binding protein homologous protein-mediated pathway. In addition, Golgi fragmentation was observed in the process. On the other hand, it was also demonstrated, in a primary neuronal-astroglial co-culture system, that the overexpression of α-syn significantly decreased the levels of glia-derived neurotrophic factor (GDNF) and partly inhibited neurite outgrowth. Although direct evidence is currently lacking, it was proposed that dysfunction of the ER-Golgi compartment in astrocytes overexpressing α-syn may lead to a decline of GDNF levels, which in turn would suppress neurite outgrowth. Taken together, the results of the present study offer further insights into the pathogenesis of PD from the perspective of astrocytes, which may provide novel strategies for the diagnosis and treatment of PD in the future.