自噬/溶酶体途径在帕金森病发生发展中的角色

帕金森病是一种以黑质纹状体区多巴胺能神经元进行性缺失和纹状体多巴胺含量显著减少为特征的中枢神经系统变性疾病.近年来,蛋白质的降解障碍被认为是帕金森病发病过程中的重要因素,自噬辕溶酶体途径是细胞内一种重要的蛋白降解途径,负责胞内泛素原蛋白酶体系统未能降解的大分子物质.自噬功能的失调和神经元的退行有重要的联系,自噬在清除与...     

自噬在帕金森病发病机制中的研究进展CSCD

自噬(autophagy)是一种降解和回收细胞成分的依赖溶酶体的高度保守过程,是细胞的主要降解途径之一。自噬可以形成特殊的双层膜结构对细胞核内物质进行降解,维持细胞内稳态。帕金森病(Parkison's disease,PD)是一种以锥体外系功能障碍为典型特征的神经系统退行性疾病,多发于60岁以上的老年人,但其发病机制尚不十分明确。目前研究较多、较为公认的有氧化应激假说和多巴胺(dopamine,DA)假说等。临床上一般采用左旋多巴缓解PD患者的症状,但却不能治愈患者,也无法阻止黑质-纹状体DA神经元细胞进行性坏死。     

自噬功能与帕金森病

自噬是广泛存在于真核细胞内的一种溶酶体依赖性降解途径,是细胞进行自我保护的一种重要机制,在维持细胞存活、更新、物质再利用和内环境稳定中起着重要作用。但是,在某些情况下自噬还可导致细胞死亡,被认为是区别于细胞凋亡     

免疫治疗帕金森病:一种新型治疗策略

针对α-突触核蛋白(α-synuclein)的疫苗是治疗帕金森病(PD)的新方法。由于α-突触核蛋白是一种胞内蛋白,一般认为,异常的α-突触核蛋白无法被疫苗产生的抗体发现,但美国学者用人α-突触核蛋白免疫的小鼠PD模型产生的抗体可识别异常α-突触核蛋白神经元细胞膜,并通过溶酶体降解途径进行破坏。这可能是治疗PD的全新方法。PD是黑质多巴胺能神经元进行性缺失的常见神经变性疾病。目前还只是对症治疗。最近发现,可溶性α-突触核蛋白与不溶性纤维聚合是PD发病的核心。这些纤维聚积在Lewy小体PD病理位点和其他疾病的Lewy小体内。针对β-淀粉…     

泛素羧端水解酶L1(UCH-L1)变体S18Y与帕金森病风险降低密切相关

[英]/Belin AC…∥Parkinsonism Relat Disord.-2007,13.-295～298泛素羧端水解酶L1(UCH-L1),也称PGP9.5,是一种神经元特异的酶类,是脑里含量最丰富的蛋白之一,在脑可溶性蛋白中占到1%～2%。UCH-L1的主要功能是从底物的碳端水解泛素,属于泛素蛋白酶家族。在神经退行性疾病中,脑黑质部位残存的多巴胺细胞嗜酸性胞浆Lewy小体中检测到UCH-L1的免疫反应活性。小鼠UCH-L1缺失导致神经退行性疾病细长形神经轴突营养不良(gad),但是gad小鼠不会发展成帕金森病(PD)表型。UCH-L1和蛋白降解有关,在人脑里丰度高,尤其是在Lewy小体中出现,…     

自噬在帕金森病发病机制中的研究进展

<正>自噬(autophagy)是一种降解和回收细胞成分的依赖溶酶体的高度保守过程,是细胞的主要降解途径之一~([1-2])。自噬可以形成特殊的双层膜结构对细胞核内物质进行降解,维持细胞内稳态。帕金森病(Parkison’s disease, PD)是一种以锥体外系功能障碍为典型特征的神经系统退行性疾病,多发于60岁以上的老年人,但其发病机制尚不十分明确。目前研究较多、较为公认的有氧化应激假说和多巴胺(dopamine, DA)假说等。临床上一般采     

海藻糖治疗帕金森病的作用机制研究进展

帕金森病是一种常见的神经变性疾病,特征性病理改变主要是黑质多巴胺能神经元丢失和路易小体的形成。路易小体中主要成分是纤维化的α-突触核蛋白,研究表明多巴胺能神经元中异常的蛋白质沉积可能与溶酶体自噬途径的失调有关。自噬调节剂的治疗潜力已在帕金森病动物模型中得到证实。海藻糖是一种天然双糖,被认为是治疗神经退行性疾病的新候选药物。它具有类似伴侣活性,防止蛋白质错误折叠或聚集,并有助于通过促进自噬去除积聚的蛋白质。总结异常自噬在帕金森病疾病发展过程中的潜在机制,讨论使用海藻糖对抗帕金森病的促进自噬、蛋白质稳定和抗神经炎症作用。     

神经酰胺调节自噬研究进展

神经酰胺(ceramide,Cer)作为具有生理活性的脂质信使,参与了细胞各种信号通路,如细胞增殖、炎症、凋亡、迁移、衰老、转移和自噬等,其合成、代谢及信号转导失调均可导致多种人类疾病,特别是在肿瘤发生、发展中具有重要作用。自噬是依赖溶酶体途径对细胞内受损细胞器、错误折叠蛋白和侵入胞内的病原体等物质进行降解的生物学过程,在细胞感染、癌变、神经变性、衰老等病理性损伤中具有调节作用。Cer作为脂代谢核心     

内质网应激相关细胞自噬与心肌缺血再灌注损伤的研究现状

自噬是细胞对自身长寿命蛋白、冗余蛋白或破坏的细胞器进行降解并再利用的过程。内质网应激是细胞的一种适应性机制,通过未折叠蛋白反应等细胞活动来维持内质网的稳态。这两者都具有双刃剑的作用:即适度的激活可以保护细胞;但过度激活则导致细胞死亡。内质网应激可以诱导细胞自噬,且与心肌缺血再灌注损伤关系密切。本文对内质网应激相关自噬在心肌缺血再灌注损伤中的作用机制及研究进展进行综述。     

自噬在白血病中的相关研究

自噬现象广泛存在于真核细胞中,且参与细胞的生理和病理过程。真核细胞存在着两大主要的蛋白质降解途径：蛋白酶体和溶酶体途径。自噬作为溶酶体降解途径之一,对于长寿蛋白降解和细胞器的重新利用发挥了重要的作用。细胞通过自噬获得可供生物体合成的氨基酸以及其它的大分子物质;另一方面．自噬也能导致细胞死亡引起Ⅱ型程序性细胞死亡,研究证明自噬的发生受不同基因的调控,如ATG（autophagy）基因、磷酸激酶基因及蛋白激酶等.     

Proteasome inhibitors protect against degeneration of nigral dopaminergic neurons in hemiparkinsonian rats

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies in the substantia nigra pars compacta (SNpc). alpha-Synuclein and ubiquitin are components of Lewy bodies, but the process of Lewy body formation and the relationship between inclusion formation and dopaminergic neuronal death have not been resolved. In this study, unilateral intranigral microinjection of 6-hydroxydopamine caused a significant loss of tyrosine hydroxylase-immunopositive neurons in both the substantia nigra and striatum and apomorphine-induced contralateral rotation. The co-administration of proteasome inhibitors, such as lactacystin or carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132), significantly prevented both dopaminergic neurodegeneration and apomorphine-induced rotational asymmetry. Proteasome inhibitors markedly formed intracellular protein inclusions labeled by thioflavin-S in the SNpc. Inclusion-like immunoreactivities for alpha-synuclein and ubiquitin were detected after 4 weeks. These results suggest that proteasome plays an important role in both the early phase of dopaminergic neuronal death and inclusion body formation.     

Cognitive deficits and psychosis in Parkinson's disease: a review of pathophysiology and therapeutic options

Parkinson's disease is a neurodegenerative disorder causing not only motor dysfunction but also cognitive, psychiatric, autonomic and sensory disturbances. Symptoms of dementia and psychosis are common: longitudinal studies suggest that up to 75% of patients with Parkinson's disease may eventually develop dementia, and the prevalence of hallucinations ranges from 16-17% in population-based surveys to 30-40% in hospital-based series. These cognitive and behavioural features are important in terms of prognosis, nursing home placement and mortality. The pattern of cognitive deficits in Parkinson's disease is variable, but often includes executive impairment similar to that seen in patients with frontal lesions, as well as episodic memory impairment, visuospatial dysfunction and impaired verbal fluency. The most common manifestation of psychosis in Parkinson's disease is visual hallucinations, but delusions, paranoid beliefs, agitation and florid psychosis can also occur. An understanding of the pathophysiology underlying these symptoms is essential to the development of targeted therapeutic strategies. Post-mortem studies suggest an association between Lewy body deposition and dementia in Parkinson's disease, and indeed Parkinson's disease and dementia with Lewy bodies may form part of the same disease spectrum. Whether Lewy bodies actually play a causative role in cognitive dysfunction, however, is unknown. Deficits in neurotransmitter systems provide more obvious therapeutic targets and dysfunction of dopaminergic, cholinergic, noradrenergic and serotonergic systems have all been implicated; these may each underlie different features of Parkinson's disease dementia, perhaps explaining some of the heterogeneity of the syndrome. Psychosis has traditionally been considered as a dopaminergic drug-induced phenomenon, but factors intrinsic to the disease process itself also cause hallucinations and delusions. These factors may include Lewy body deposition in the limbic system, cholinergic deficits and impairments of primary visual processing. Therapeutic intervention for cognitive and behavioural symptoms in Parkinson's disease currently focuses on two main groups of drugs: cholinesterase inhibitors and atypical antipsychotics. A recent large, randomised, controlled trial suggests that cholinesterase inhibitors can produce a modest improvement in cognitive function, as well as psychotic symptoms, generally without an adverse effect on motor function. Certain atypical antipsychotics allow hallucinations, delusions and behavioural problems to be brought under control with minimal deleterious effects on motor function and cognition, but their safety in elderly patients has recently been called into question. Deep brain stimulation does not appear to be a useful treatment for cognitive and psychiatric dysfunction in patients with Parkinson's disease. Modafinil improves alertness in Parkinson's disease and warrants further investigation to establish its effects on cognitive performance.     

From neurodegeneration to neurohomeostasis: the role of ubiquitin

Several years ago ubiquitin immunocytochemistry first demonstrated that ubiquitin protein conjugates are present in intraneuronal inclusions in all the major human chronic neurodegenerative diseases, as well as in inclusions in cerebellar astrocytomas and in hepatocytes in alcoholic liver disease. Unexpectedly, further studies showed that Lewy bodies are present in the cortex. Lewy bodies were originally described in the brain stem and are pathogonomic in the neuropathological diagnosis of Parkinson's disease. A balanced interpretation of further elegant experimental approaches, including transgenesis, suggests that the formation of intraneuronal inclusions is cytoprotective. Putative oligomeric proaggregates (prefibrillar entities) of cellular proteins inhibit the 26S proteasome and promote apoptosis. In the last few years a clutch of distinct experimental approaches have focused on the roles of ubiquitin-related processes in the development of the nervous system and neurohomeostasis. It is now clear that the ubiquitin/proteasome system (UPP) has a pivotal role in synaptogenesis, the formation of neuromuscular junctions and neurotransmitter receptor function. The inhibitory GABA(A) receptor, alpha1 glycine receptor, beta(2)-adrenergic receptor and arrestin, opiate receptors and the excitatory metabotropic glutamate receptor (mGluR1alpha) are regulated by the UPP. It is also increasingly clear that the regulation of long-term synaptic plasticity, and therefore memory, is dependent on both protein synthesis and protein degradation. Therefore, for the first time we have the opportunity to dissect the substrate of memory and the basis of cognitive decline in aging and in chronic neurodegenerative disease. Clearly, further understanding will provide a platform for novel drug development to treat chronic neurodegenerative diseases, including Alzheimer- and Parkinson-related conditions, and possibly psychiatric disorders.     

Minocycline: neuroprotective mechanisms in Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by cardinal features of tremor, bradykinesia, rigidity and postural instability. In addition to the motor symptoms patients experience cognitive decline eventually resulting in severe disability. Pathologically PD is characterized by neurodegeneration in the substantia nigra pars compacta (SNc) with intracytoplasmic inclusions known as Lewy bodies. In addition to the SNc there is neurodegeneration in other areas including cerebral cortex, raphe nuclei, locus ceruleus, nucleus basalis of meynert, cranial nerves and autonomic nervous system. Recent evidence supports the role of inflammation in Parkinson's disease. Apoptosis has been shown to be one of the pathways of cell death in PD. Minocycline, a tetracycline derivative is a caspase inhibitor, and also inhibits the inducible nitric oxide synthase which are important for apoptotic cell death. Furthermore, Minocycline has been shown to block microglial activation of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonism animal models and protect against nigrostriatal dopaminergic neurodegeneration. In this review, we present the current experimental evidence for the potential use of tetracycline derivative, minocycline, as a neuroprotective agent in PD.     

CYP2D6 is associated with Parkinson's disease but not with dementia with Lewy Bodies or Alzheimer's disease

The similarities between the clinical and pathological findings of dementia with Lewy Bodies (DLB) with Alzheimer's disease and Parkinson's disease are complex, and their significance for pathogenesis is unresolved. It is likely that DLB shares common disease determinants with both Alzheimer's disease and Parkinson's disease. Clinically DLB shows the presence of dementia similar, though not identical, to that found in Alzheimer's disease. A parkinsonian movement disorder is present in a proportion of DLB cases. Pathologically DLB shows senile plaques, as with Alzheimer's disease, and also substantia nigra neurone loss and Lewy bodies, as with Parkinson's disease. At a genetic level, DLB shows an elevated Apolipoprotein E epsilon4 frequency as described in Alzheimer's disease, but this is absent in Parkinson's disease. An elevated frequency of the CYP2D6*4 allele has been found in Parkinson's disease and we have therefore genotyped a large series of clinically and neuropathologically confirmed cases of DLB, Alzheimer's disease, Parkinson's disease and age-matched control individuals for the CYP2D6*4 allele. Whilst an elevated frequency of the CYP2D6*4 allele was found in Parkinson's disease, no such elevations were found in DLB or Alzheimer's disease. Stratification of the CYP2D6*4 allele with respect to the Apolipoprotein E epsilon4 also did not show any significant associations with the CYP2D6*4 allele. The CYP2D6*4 allele is not a major genetic determinant of DLB and the results place DLB with Alzheimer's disease rather than Parkinson's disease on a genetic level.     

少突胶质细胞在帕金森病中的研究进展

少突胶质细胞(oligodendrocytes,OLs)是中枢神经系统(central nervous system,CNS)中的神经胶质细胞之一,由少突胶质前体细胞(oligodendrocyte precursor cells,OPCs)分化而成,能够形成绝缘性髓鞘,促进轴突动作电位的快速传导。帕金森病(parkinson’s disease,PD)是以黑质纹状体多巴胺能神经元丢失为特征的CNS退行性疾病,其病理标志为嗜酸性路易小体(Lewy bodies,LBs)和路易神经突(Lewy neurites,LNs)的聚集,其中,LBs的主要成分为错误折叠的α-突触核蛋白(α-synuclein,α-syn)。研究发现,许多PD患者具有脱髓鞘、白质病变、OLs损伤等伴随病理表现,此外,OLs中聚集的α-syn能够加速神经元的死亡,提示OLs在PD的发生发展过程中起着重要的作用。因此,深入研究OLs与PD的关系有助于进一步探索PD的发病机制,为发现新的PD治疗靶点提供新思路,有望通过维持髓鞘完整性、保证OLs的正常功能而干预PD的病理进展。     

Neurochemistry changes associated with mutations in familial Parkinson's disease

Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.     

Neurodegenerative pathways in Parkinson's disease: therapeutic strategies

Parkinson's disease (PD), considered one of the major neurological disorders, is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by the presence of intraneuronal cytoplasmic inclusions called Lewy bodies. The causes for degeneration of PD neurons remain unclear, however, recent findings contributed to clarify this issue. This review will discuss the current understanding of the mechanisms underlying Parkinson's disease pathogenesis, focusing on the current and potential therapeutic strategies for human treatment.     

Glutathione,iron and Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disease involving neurodegeneration of dopaminergic neurons of the substantia nigra (SN), a part of the midbrain. Oxidative stress has been implicated to play a major role in the neuronal cell death associated with PD. Importantly, there is a drastic depletion in cytoplasmic levels of the thiol tripeptide glutathione within the SN of PD patients. Glutathione (GSH) exhibits several functions in the brain chiefly acting as an antioxidant and a redox regulator. GSH depletion has been shown to affect mitochondrial function probably via selective inhibition of mitochondrial complex I activity. An important biochemical feature of neurodegeneration during PD is the presence of abnormal protein aggregates present as intracytoplasmic inclusions called Lewy bodies. Oxidative damage via GSH depletion might also accelerate the build-up of defective proteins leading to cell death of SN dopaminergic neurons by impairing the ubiquitin-proteasome pathway of protein degradation. Replenishment of normal glutathione levels within the brain may hold an important key to therapeutics for PD. Several reports have suggested that iron accumulation in the SN patients might also contribute to oxidative stress during PD.     

Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease

Alpha-synuclein (alphaSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer's disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as alpha-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of alphaSN. This molecular form of alphaSN contrasts sharply with normal alphaSN, which is an abundant soluble presynaptic protein in brain neurons. alphaSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an alphaSN gene. Implicated in neurotoxicity are two alphaSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, alphaSN fibrils and protofibrils, soluble protein complexes of alphaSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated alphaSN species. Unlike rare forms of fPD caused by mutations in alphaSN, disease mechanisms in most alpha-synucleinopathies implicate wildtype alphaSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve alphaSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic alphaSN forms damage neurons. Here, we summarize the main structural features of alphaSN and its functions, and discuss the molecular alphaSN species implicated in human disease and transgenic animal models of alpha-synucleinopathy in fly and rodents.