葛根素调节PINK1/parkin信号通路对横纹肌溶解致大鼠急性肾损伤的影响

目的 探讨葛根素是否可通过调节PTEN诱导激酶1/帕金森病相关基因(PINK1/parkin)信号通路影响横纹肌溶解诱导的急性肾损伤大鼠线粒体自噬。方法 将60只SPF级成年雄性SD大鼠分为正常组(等量生理盐水)、模型组(50%甘油10 mL/kg)、葛根素低剂量组(葛根素50 mg/kg)、葛根素中剂量组(葛根素100 mg/kg)、葛根素高剂量组(葛根素200 mg/kg)、3-MA组(腹腔注射3-MA 15 mg/kg),每组10只。3-MA组灌胃葛根素200 mg/kg同时腹腔注射15 mg/kg自噬抑制剂3-MA,各给药组连续灌胃给药7 d后,除正常组外其余各组大鼠在双侧后肢肌肉一次性注射50%甘油10 mL/kg,建立横纹肌溶解诱导的急性肾损伤大鼠模型。血清生化分析血清尿素氮(BUN)、肌酐(SCr)和肌酐磷酸激酶(CK)水平;ELISA法检测血清肿瘤坏死因子α(TNF-α)、白介素1β(IL-1β)、白介素6(IL-6)水平;HE染色法观察大鼠肾组织病理变化;试剂盒法测量大鼠肾脏组织超氧化物歧化酶(SOD)、谷胱甘肽(GSH)、丙二醛(MDA)、活性氧(ROS)水平;透射...     

早发帕金森病临床特征、多巴转运体PET显像及基因突变分析

目的探讨早发帕金森病的临床特征、多巴胺功能改变和基因突变。方法选取作者医院收治的10例早发帕金森病患者(男、女各5例),发病年龄平均(31.4±8.0)岁,平均病程(3.0±0.8)年,无家族史,对所有患者的临床资料、多巴转运体PET显像及基因检测结果进行回顾性分析。结果 10例患者均有受累肢体运动迟缓及肌张力增高,6例出现静止性震颤,5例有足部肌张力障碍,4例腱反射活跃,2例腱反射亢进,4例存在日间症状波动。3例伴抑郁。9例患者对多巴丝肼反应良好。8例进行脑多巴胺转运体PET显像(11 C-CFT DATPET)检查,1例起病对侧壳核后部DAT降低,7例显示双侧壳核后部DAT降低,其中4例起病对侧DAT降低更为明显。1例parkin基因3、4外显子缺失,PINK1基因外显子1还发生重复突变。1例parkin基因外显子4出现了纯合突变。3例parkin基因外显子3或4发生杂合突变。结论早发帕金森病具有独特的临床特征,纹状体多巴胺功能发生改变,parkin基因和PINK1基因与其发病相关。     

Parkin蛋白与帕金森病

分子遗传学研究证明parkin基因是常染色体隐性遗传性少年型帕金森综合征(AR-JP)的致病基因，其表达产物parkin蛋白具有E3泛素-蛋白连接酶活性。Parkin蛋白可能在维持多巴胺能神经元的正常功能中发挥重要作用，而parkin蛋白功能障碍可能与帕金森病的发病有关。目前已经鉴定了几种parkin蛋白的底物蛋白，使我们能够初步了解帕金森病发病的分子和细胞学机理，这对于我们最终搞清帕金森病的发病机制、开发相应的治疗药物具有极其重要的意义。本文综述了parkin蛋白最新研究进展。     

Parkin expression reverses mitochondrial dysfunction in fused in sarcoma‐induced amyotrophic lateral sclerosis

Fused in sarcoma (FUS) is a DNA/RNA‐binding protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. The exact molecular mechanisms by which FUS results in neurotoxicity have not yet been fully elucidated. Here, we found that parkin is a genetic suppressor of defective phenotypes induced by exogenous human wild type FUS in Drosophila. Although parkin overexpression did not modulate the FUS protein expression level, the locomotive defects in FUS‐expressing larvae and adult flies were rescued by parkin expression. We found that FUS expression in muscle tissues resulted in a reduction of the levels and assembly of mitochondrial complex I and III subunits, as well as decreased ATP. Remarkably, expression of parkin suppressed these mitochondrial dysfunctions. Our results indicate parkin as a neuroprotective regulator of FUS‐induced proteinopathy by recovering the protein levels of mitochondrial complexes I and III. Our findings on parkin‐mediated neuroprotection may expand our understanding of FUS‐induced ALS pathogenesis.     

Neuropathological findings in benign tremulous Parkinsonism

Benign tremulous parkinsonism, a tremor dominant syndrome with a relatively slow rate of deterioration, is recognized by clinicians although its pathological basis is not well understood. A systematic review of Queen Square Brain Bank donors was carried out to determine the natural history and pathology of individuals who had tremor dominant parkinsonism with mild non‐tremor components and minimal gait disability for at least 8 years. We identified 16 cases of pathologically proved benign tremulous Parkinson's disease (PD); another 5 individuals conformed to the definition but did not have the pathology of PD. Patients with verified benign tremulous PD had less severe neuronal loss in the substantia nigra than controls (χ²: P = .003). Twelve of these had been correctly diagnosed with PD at their first neurological evaluation, whereas the other 4 were originally thought to have another tremor disorder. The only consistent distinguishing feature of the 5 pathologically disproved cases, who may have had either essential tremor with associated rest tremor or dystonic tremor, was a failure to develop unequivocal bradykinesia within a decade of onset of tremor at rest. Our findings support the existence of a distinct subgroup of benign tremulous PD. The slower rate of clinical progression correlates with less severe nigral cell loss at postmortem, although many of these patients transgress the benign tremulous parkinsonism definition by the final third of their disease course and develop the common features of advanced PD. © 2012 Movement Disorder Society     

Non-mammalian animal models of Parkinson's disease for drug discovery

Importance of the field: Parkinson's disease (PD) is a prevalent neurodegenerative disease affecting millions of predominantly elderly individuals worldwide. Despite intensive efforts devoted to drug discovery, the disease remains incurable. Compounding this problem is the current lack of a truly representative mammalian model of PD. However, a number of non-mammalian models of PD have been created in recent years that hold tremendous promise to accelerate our understanding of the disease as well as to transform the drug discovery process.

Areas covered in this review: This review provides an overview of the various Caenorhabditis elegans and Drosophila genetic models of PD that have been generated to date and discusses the utility of these model systems in the identification of molecules of potential therapeutic value for the PD patient.

What the reader will gain: Readers will appreciate the strengths (and limitations) of C. elegans and Drosophila in modeling salient features of the disease as well as their usefulness in uncovering novel gene–gene interaction and pathways relevant to PD pathogenesis. Readers will also appreciate how technological advancements have allowed the direct evaluation of novel compounds in these living models of PD in a virtually high-throughput manner.

Take home message: Non-mammalian models of PD provide a valuable in vivo platform for drug screening. Unlike cell-based systems, these living models with an intact nervous system allow for a more meaningful evaluation of the neuroprotective properties of genetic and chemical modifiers to be conducted.     

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.     

Structural studies of parkin and sacsin: Mitochondrial dynamics in neurodegenerative diseases

Neurodegenerative diseases are prevalent, chronic diseases emanating from the dysfunction or death of neurons. The disrupted mitochondrial dynamics observed in a large number of neurodegenerative diseases suggests a common etiology with the possibility of therapies targeting multiple diseases. This review highlights the contributions of structural studies of disease‐related proteins to the understanding of neurodegenerative disease pathogenesis and especially the cellular events leading to disruptions in mitochondrial dynamics and function. The examples used are parkin and sacsin, two proteins linked respectively to autosomal‐recessive early‐onset PD and autosomal‐recessive spastic ataxia of Charlevoix‐Saguenay. Structural studies of parkin and sacsin explain the pathogenicity of a large number of disease‐associated mutations and reveal insights into their cellular functions related to mitochondrial dynamics. © 2015 International Parkinson and Movement Disorder Society     

Peripheral neuropathy and parkinsonism: a large clinical and pathogenic spectrum

Peripheral neuropathy (PN) has been reported in idiopathic and hereditary forms of parkinsonism, but the pathogenic mechanisms are unclear and likely heterogeneous. Levodopa‐induced vitamin B12 deficiency has been discussed as a causal factor of PN in idiopathic Parkinson's disease, but peripheral nervous system involvement might also be a consequence of the underlying neurodegenerative process. Occurrence of PN with parkinsonism has been associated with a panel of mitochondrial cytopathies, more frequently related to a nuclear gene defect and mainly polymerase gamma (POLG1) gene. Parkin (PARK2) gene mutations are responsible for juvenile parkinsonism, and possible peripheral nervous system involvement has been reported. Rarely, an association of parkinsonism with PN may be encountered in other neurodegenerative diseases such as fragile X‐associated tremor and ataxia syndrome related to premutation CGG repeat expansion in the fragile X mental retardation (FMR1) gene, Machado–Joseph disease related to an abnormal CAG repeat expansion in ataxin‐3 (ATXN3) gene, Kufor–Rakeb syndrome caused by mutations in ATP13A2 gene, or in hereditary systemic disorders such as Gaucher disease due to mutations in the β‐glucocerebrosidase (GBA) gene and Chediak–Higashi syndrome due to LYST gene mutations. This article reviews conditions in which PN may coexist with parkinsonism.