PINK1基因与帕金森病

帕金森病（Parkinson＇s disease，PD）是一种常见的神经系统退行性疾病，病理以黑质多巴胺能神经元的丧失和路易体（Lewy body）的形成为特点。大多数PD患者无家族史，约15％患者有家族史。研究已发现11个染色体定位以孟德尔遗传方式与PD连锁，其中5个呈常染色体显性（autosomal dominant，AD）遗传，4个呈常染色体隐性（autosomal recessive，AR）遗传（表1）。到目前为止，已有6个致病基因被克隆，它们是常染色体显性遗传性PD（综合征）的致病基因α-synuclein基因，UCH-L1基因和LRRK2基因；常染色体隐性遗传性PD（综合征）的致病基因parkin基因，DJ-1基因和PINK1（PTEN-induced putative kinase-1）基因。目前的研究发现，PINK1基因在常染色体隐性遗传性PD（综合征）患者中的突变率仅次于parkin基因，而其编码的PINK1蛋白是第一个将线粒体功能异常与遗传性PD（综合征）联系起来的蛋白。     

家族性帕金森病的基因研究进展（综述）

回顾了近年来家族性帕金森病（Parkinson disease,PD)的基因研究最新进展,第4号染色体长臂上的α－synuclein基因在第4号外显子上的1个错义点突变（G209A）,导致其编码的氨基酸序列上的53位氨基酸由丙氨酸（Ala)突变为苏氨酸（Thr,A53T),从而发生聚集,缠绕和纤维化,致使多巴胺神经元死亡,青年型PD综合征与第6号染色体长臂6q25.2-27之间的一个称为Parkin的基因密切相关,其第3－7号外显子的不规则缺失突变,导致Parkin丧失运输有缺陷的或已失活蛋白的能力,还有可能导致其丧失细胞生长,分化和发育的调控功能,最终表现为多巴胺神经元死亡和缺失,对位于第2号染色体短臂上的Park3基因的研究,虽然其具体机制不清楚,但可能为散发性PD的研究提供一些启示。     

α-突触核蛋白在帕金森病发病机制中的作用

帕金森病（Parkinson disease，PD）是一种常见于中老年期的慢性进展的神经系统变性疾病，其病因及发病机制尚不完全清楚，目前认为可能是遗传因素与环境因素共同作用的结果。自1997年从常染色体显性遗传家族性PD中发现α-突触核蛋白（α-synuclein）氨基末端两个罕见的错义突变（A30P和A53T）后，α-synuclein引起了广泛的关注。α-synuclein是淀粉样斑块（NAC）的前体蛋白（NACP），在神经组织中广泛表达。目前有关α-synuclein的结构与功能、α-synuclein与PD关系的研究层出不穷。α-synuclein在PD的发病机制中究竟扮演了什么角色？我们对目前有关研究作一综述。     

大麻素受体1在帕金森病大鼠基底节表达的研究

目的：观察6-OHDA单侧毁损帕金森病（PD）大鼠模型基底节内大麻素受体1（CBR1表达特点，探讨其与PD的关系。方法：6-OHDA两点法立体定向单侧前脑内侧束（MFB）注射建立PD大鼠模型，采用免疫组化（IHC）和Western blot方法检测基底节内CBR1的表达水平。结果：IHC显示CBR1在大鼠基底节内广泛表达，PD组患侧纹状体（CPU）和苍白球（GP）CBR1较对照组显著增多（均P〈0、01）；但PD组患侧黑质网状部（SNr）CBR1较对照组明显减少（P〈0.01）。Western blot结果同IHC一致：PD组患侧CPU内CBR1较对照组显著增多（P〈0、01）。结论：PD时基底节内CBR1系统信号传导改变可能对PD的病理生理发展有重要调控作用。     

α-核突触蛋白和自噬在帕金森病中的作用

α-核突触蛋白（α-synuclein）是路易小体的重要组分与帕金森病（PD）发病机制密切相关,如何调控其表达一直是阐明其致病机制以及防治的研究热点。在蛋白质量调控系统巾,泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP）都参与了仪一核突触蛋白的降解。在老化、外源性毒素和基因突变等情况下,UPS和ALP都可以被诱导。如果上述两条途径,尤其是自噬出现功能障碍就会导致神经变性和细胞死亡。因而,通过调控自噬进而促进易聚集蛋白α-核突触蛋白的清除成为延缓PD疾病进展的一个潜在治疗靶点。     

组蛋白去乙酰化酶6与神经变性疾病北大核心CSCD

神经变性疾病是一组由于中枢神经系统特定区域神经元发生变性而引起的慢性进行性疾病,主要包括帕金森病（Parkinson＇s disease,PD）、阿尔茨海默病（Alzheimer’s disease,AD）和亨廷顿舞蹈病（Huntington’s disease,HD）等,这些疾病均以异常蛋白质聚集和神经元选择性丢失为特征。虽然细胞自身具备清除这种蛋白质的途径,但是当其产生速度超过清除速度时,将会聚集并干扰细胞的正常功能。因此,寻找降解异常蛋白质的有效途径,对于治疗神经变性疾病具有重要意义。     

Fe3+与PC12细胞α-synuclein蛋白聚集关系的研究

近年研究表明，α-synuclein蛋白的聚集可能在帕金森病(Parkinson disease，PD)的发病中起到重要作用，因此，了解该蛋白发生聚集的原因对进一步明确PD的发病机制有重要意义。体外实验发现，氧化应激可以使重组的野生型α-synuclein蛋白发生聚集；众所周知，PD患者中脑部位铁水平增高，铁能够介导氧化还原反应造成氧化应激状态，因此，我     

CaMK Ⅱ在跑步机训练改善帕金森病模型小鼠记忆功能中的作用

目的 研究钙离子/ 钙调蛋白激酶Ⅱ（CaMK Ⅱ）在跑步机训练改善帕金森病（PD）模型小鼠 记忆功能中的分子机制，为PD的治疗提供一个新的思路。方法 将6-羟基多巴胺立体定向注射至小 鼠左侧纹状体内制备偏侧PD小鼠模型，利用圆柱体实验筛选PD 模型。将造模成功的PD小鼠（n=32）随 机分为PD 非跑步机训练组（PD+no-Ex 组，n=8）、低速跑步机训练组（PD+Low-Ex，n=8）、中速跑步机训练 组（PD+Medium-Ex，n=8）和高速跑步机训练组（PD+High-Ex，n=8），并设Sham 组（n=8，在相同部位注射 生理盐水）作为对照。利用Morris水迷宫实验观察各组小鼠的学习记忆能力，并对其行为学结果进行分 析评价，选取Sham组、PD+no-Ex 组及PD+Low-Ex 组海马组织，利用Western blot 检测小鼠海马中环磷腺 苷效应元件结合蛋白（CREB）、酪氨酸羟化酶（TH）、细胞外信号调节蛋白激酶1/2（ERK1/2）和CaMK Ⅱ的 磷酸化水平。结果 Morris水迷宫定位航行实验结果表明各组小鼠的平均逃避潜伏期随着训练时间的 延长呈逐渐下降趋势，低中高速跑步机训练都有利于PD 小鼠记忆功能的恢复（P＜ 0.05），但低速跑步机 训练组小鼠改善得更明显（P＜ 0.05）。空间探索实验结果则表明，与Sham组比较，PD+no-Ex 组小鼠穿 越平台次数明显减少，差异有统计学意义（P＜ 0.05）；与PD+no-Ex 组比较，不同速度跑步机训练组小鼠 穿越平台次数明显增加，差异有统计学意义（P＜ 0.05）。Western blot 结果显示，与Sham 组比较，PD+no- Ex 组磷酸化CREB、ERK1/2、CaMK Ⅱ及TH水平明显降低，差异均有统计学意义（P ＜ 0.05）；与PD+no- Ex 组比较，PD+Low-Ex 组上述指标明显升高，差异均有统计学意义（P＜ 0.01）。结论 低速跑步机训练 对PD 模型小鼠学习记忆能力的改善作用更显著，其可能是通过上调海马中蛋白激酶A（PKA）介导的信 号转导通路，从而改善PD小鼠的认知功能。     

调控小胶质细胞——帕金森病药物研发的新方向(述评)

帕金森病（Parkinsondisease，PD）是中老年人常见的中枢神经系统（CNS）退行性疾病，目前呈逐年增长趋势。随着对PD发病机制研究的不断深入，学者们已逐渐认识到小胶质细胞在PD发病和病情进展中的重要地位，调控小胶质细胞无可替代地成为PD药物研发的新方向之一。     

帕金森病与LRRK2基因R1441C、R1441G突变相关性

帕金森病（Parkinson disease．PD）是一种常见的神经系统退行性变性疾病，临床主要表现为静止性震动、肌强直、运动迟缓、姿势反射障碍。随着α—synuclein，parkin、UCH-LI、PINKI 、DJ—I、LRRK2等PD致病基因的相继克隆。遗传因素在PD发病机制中的作用越来赵受到关注．目前有关LRRK2基因（PARK8）的研究，国外报道的文献不多．目内尚未有文献报道，我们于2004年12月至2005年3月对所收集的中国常染色体显性遗传性PD家系和散发的PD患者进行研究，筛查是否存在LRRK2基因的R1441G和R1441C这两个错义突变．     

Use of viral vectors to create animal models for Parkinson's disease

Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. While sporadic in the majority of cases, PD-linked dominant mutations in the α-synuclein and LRRK-2 genes, and recessive mutations in the parkin, DJ-1 and PINK-1 genes have been identified in PD families in recent years. In this review we describe viral animal models for PD, i.e. models that are based on PD-associated mutations, and have been generated by viral delivery of the respective disease genes to the substantia nigra of rodents and non-human primates. To date, viral PD models comprise α-synuclein and LRRK-2-based overexpression models, as well as models that mimic parkin loss of function by overexpression of the parkin substrates Pael-R, CDCrel-1, p38/JTV or synphilin-1. These viral models provide valuable insights into Parkinson disease mechanisms, help to identify therapeutic targets and may contribute to the development of therapeutic approaches.     

Autosomal dominant Parkinson’s disease

Multiple factors have been hypothesized over the years to be contributory and or causative for Parkinson’s disease (PD). Hereditary factors, although originally discounted, have recently emerged in the focus of PD research. The study of a large Italian family with PD using a genome scan approach led to the mapping of a PD susceptibility gene to the 4q21-q23 genomic region, where the gene for α-synuclein was previously mapped. Mutation analysis of the α-synuclein in four unrelated families with PD revealed a missense mutation segregating with the illness. α-Synuclein is an abundant presynaptic protein of the human brain of unknown function. It is conceivable that the mutation identified in the PD families may result in self-aggregation and or decreased degradation of the protein, leading to the development of intracytoplasmic inclusion bodies and eventually to neuronal cell death. Moreover, the discovery of a mutation in the synuclein gene may offer us new insights into the understanding of the pathways that lead to neuronal degeneration.

     

The α-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: A study of 230 European cases

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the α-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.     

α-Synuclein multiplication analysis in Italian familial Parkinson disease

The α-synuclein gene (SNCA) multiplication causes autosomal dominant Parkinson Disease (PD): triplication is associated with early-onset rapidly progressing parkinsonism with a strong likelihood of developing dementia, while duplication is associated with a less severe phenotype similar to idiopathic PD.We tested for SNCA multiplication 144 unrelated PD patients with a dominant family history. We identified one patient with SNCA duplication (0.7%).The SNCA-duplicated patient was a woman of 45 years of age with PD onset at 41 years of age. She experienced a rapidly progressive disease with early motor complications (on/off fluctuations and dyskinesias). Medical records confirmed that the proband's mother developed PD at 47 years of age and died at 63 with dementia. She experienced rapid progression in both motor and cognitive symptoms: development of dementia at 54 years of age, 7 years after onset.Although SNCA duplication is an unusual cause of familial PD testing for it is worthwhile. The clinical presentation of duplicated cases may be more aggressive than usual.     

α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy?

We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.     

α-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson disease

Parkinson disease (PD) is the most common movement disorder. It is characterized by bradykinesia, postural instability, resting tremor, and rigidity associated with the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Another pathological hallmark of PD is the presence of α-synuclein proteiniacous inclusions, known as Lewy bodies and Lewy neurites, in some of the remaining dopaminergic neurons. Mounting evidence indicates that both genetic and environmental factors contribute to the etiology of PD. For example, genetic mutations (duplications, triplications or missense mutations) in the α-synuclein gene can lead to PD, but even in these patients, age-dependent physiological changes or environmental exposures appear to be involved in disease presentation. Several additional alterations in many other genes have been established to either cause or increase the risk of parkinson disease. More specifically, autosomal dominant missense mutations in the gene for leucine-rich repeat kinase 2 (LRRK2/PARK8) are the most common known cause of PD. Recently it was shown that G2019S, the most common diseasing-causing mutant of LRRK2, has dramatic effects on the kinase activity of LRRK2: while activity of wild-type LRRK2 is inhibited by manganese, the G2019S mutation abrogates this inhibition. Based on the in vitro kinetic properties of LRRK2 in the presence of manganese, we proposed that LRRK2 may be a sensor of cytoplasmic manganese levels and that the G2019S mutant has lost this function. This finding, alongside a growing number of studies demonstrating an interaction between PD-associated proteins and manganese, suggest that dysregulation of neuronal manganese homeostasis over a lifetime can play an important role in the etiology of PD.     

Low frequency of α-synuclein mutations in familial Parkinson's disease

A mutation in exon 4 of the α-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.     

Genetic influence on the development of Parkinson’s disease

In the last few years, the genetic contribution to Parkinson’s disease has gained major attention and resulted in the identification of four gene loci in autosomal dominant and autosomal recessive Parkinson’s disease. Several mutations in two genes have been shown to be responsible for neuronal cell death in Parkinsons’s disease. One of the gene products involved, α-synuclein, is a major component of Lewy bodies, the neuropathological feature of Parkinson’s disease. In contrast, mutations in the parkin gene are associated with parkinsonism without Lewy body pathology. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and of xenobiotic metabolism is technically now possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of Parkinson’s disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.

     

Autosomal dominant Parkinson's disease in a large German pedigree

Brüggemann N, Külper W, Hagenah J, Bauer P, Pattaro C, Tadic V, Lohnau T, Winkler S, Tönnies H, Sprenger A, Pramstaller P, Rolfs A, Siebert R, Riess O, Vieregge P, Lohmann K, Klein C. Autosomal dominant Parkinson’s disease in a large German pedigree.
Acta Neurol Scand: 2012: 126: 129–137.
© 2011 John Wiley & Sons A/S. Objective – While several genes have been identified to cause Parkinson′s disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late‐onset autosomal dominant PD. Methods – Thirty‐eight family members of a five‐generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD‐causing genes and a genome‐wide linkage analysis were performed. Results – Late‐onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD‐causing genes. Genome‐wide linkage analysis suggested a putative disease gene in an 11.3‐Mb region on chromosome 7p15–21.1 with a multipoint LOD score of 2.0. Conclusions – The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late‐onset PD.