尼古丁预防帕金森氏综合症和老年痴呆症的分子机理研究

吸烟有害健康,吸烟产生的自由基、亚硝胺和多环芳烃等是主要有害物质,而尼古丁是造成吸烟依赖的主要物质。流行病学统计显示,吸烟者患帕金森氏综合症(Parkinson's disease,PD)和老年痴呆症(Alzheimer's disease,AD)的概率远低于不吸烟者;实验和人群结果表明尼古丁可以预防PD和AD,但其机理还不十分清楚。实验发现:1)尼古丁可以有效清除活性氧自由基,能够抑制多巴胺自氧化,是一种抗氧化剂;2)尼古丁能够有效抑制6-OHDA和MPP 诱导的细胞色素C(Cytochrome C,Cyt.C)释放;3)尼古丁可以保护海马神经元抵抗β淀粉样蛋白诱导的凋亡;4)尼古丁可以防止淀粉样蛋白在转基因AD鼠脑中的沉淀;5)尼古丁可以络合金属铜和锌,防止其在脑中积聚;6)尼古丁可以通过激活烟碱型乙酰胆碱受体nAChRs(nicotin acetylcholine receptor)7和MAPK(mitogen activated protein kinase)来抑制NF-κB和C-Myc信号通路,抑制炎症和诱导型NOS表达和NO生成,预防AD。这些结果对于解释尼古丁防治神经退行性疾病AD和PD的机理具有重要意义。     

Aβ25-35诱导大鼠记忆力障碍与海马细胞色素氧化酶活性及线粒体超微结构的变化

目的探讨Aβ诱导模拟人类Alzheimer's病(AD)大鼠模型中海马CA1区细胞色素氧化酶的表达和神经元线粒体超微结构的变化及其与老年性记忆力减退的关系,揭示Aβ对神经元的毒性机制.方法通过将Aβ25-35注射入海马建立阿尔茨海默病动物模型,使用Y形迷宫试验检测大鼠的学习记忆能力,运用酶组织化学方法测定大鼠海马CA1区细胞色素氧化酶活性,应用电镜观察大鼠海马CA1区神经细胞线粒体超微结构的变化.结果与对照组比较,接受Aβ注射的大鼠学习记忆能力降低(P<0.05),线粒体数量及形态发生了明显的变化,海马CA1区脑组织细胞的细胞色素氧化酶活性相对于对照组也有显著的下降(P<0.05).结论 Aβ在神经退行性变中的作用可能与细胞色素氧化酶表达下降及神经元线粒体超微结构的改变导致的细胞能量代谢障碍有关.     

β淀粉样蛋白导致的线粒体损伤研究进展

阿尔茨海默病(Alzheimer disease,AD)是老年人中最常见的神经退行性疾病之一,但目前对于AD发病机制尚不清楚．越来越多的研究表明,β淀粉样蛋白 (β-amyloid,Aβ)引起的线粒体结构异常和功能损伤在AD的发病过程中发挥重要作用． Aβ引发线粒体损伤的机制主要为诱导线粒体能量代谢中几种关键酶的活性下降、线粒体分裂/融合平衡的破坏以及线粒体通透性转换孔(mitochondrial permeability transition pore, mPTP)开放．综述了Aβ引发线粒体损伤的以上几方面机制在近年来取得的进展．     

Aβ1-42注射后大鼠海马神经元凋亡及线粒体凋亡途径相关蛋白表达变化的研究

目的:研究大鼠海马注射淀粉样β蛋白(β-amyloid,Aβ)后海马神经元凋亡及线粒体凋亡途径相关蛋白表达的变化,探讨其在阿尔茨海默病发病机制与病理改变中的作用.方法:SD大鼠36只随机分为正常对照组,生理盐水组和模型组.大鼠双侧海马注射Aβ1-42越建立AD模型,不同时间点Y迷宫进行行为学测试,TUNEL法检测海马神经元凋亡表达,western-blot检测海马细胞色素C、caspase-9蛋白表达.结果:模型组大鼠术后14天达到学会标准所需电击次数较生理盐水组和正常对照组增加(P<0.05),21天、28天增加更显著(P<0.01).模型组凋亡细胞数较正常对照组、生理盐水组明显增多(P<0.01).模型组大鼠海马细胞色素C与caspase-9蛋白表达明显高于生理盐水组与正常对照组(P<0.05).结论:Aβ1-42>海马注射通过激活线粒体凋亡途径诱导海马神经元凋亡.引起大鼠学习记忆能力损害,在AD的发病机制与病理进程中发挥重要作用.     

灵芝多糖对Aβ25-35诱导阿尔茨海默病模型大鼠脑组织的保护作用

目的研究灵芝多糖(GLP)对Aβ25-35诱导阿尔茨海默病模型大鼠脑组织的影响。方法采用双侧海马内一次性注射β-淀粉样多肽25-35片段(Aβ25-35)制作大鼠AD模型,再连续7天腹腔注射GLP,随后进行行为学测定,采用HE染色、透射电镜及免疫组织化学等方法检测海马神经元的结构变化及反应性星形胶质细胞活化程度的影响。结果海马内注射Aβ25-35后海马细胞增生、聚集,核边聚、碎裂,电镜观察显示,锥体细胞胞浆水肿,内质网池扩张,星形胶质细胞增生肥大,GLP组病变显著减轻,超微结构尚属正常,海马星形胶质细胞较AD组显著减少。结论灵芝多糖对Aβ25-35诱导阿尔茨海默病模型大鼠脑组织内海马退行性变神经元有一定的保护作用,并能降低脑组织内的神经炎症反应。     

抗糖尿病新药(D-Ser2)Oxm拮抗淀粉样β蛋白细胞毒性的神经保护效应观察北大核心CSCD

淀粉样β蛋白(amyloidβ-protein,Aβ)在脑内的沉积及其神经毒性是阿尔茨海默病(Alzheimer’s disease,AD)的主要原因之一,目前仍缺乏拮抗Aβ的有效药物。最新报道表明,一种新的抗糖尿病药物(D-Ser2)Oxm不仅可以改善2型糖尿病(T2DM)大鼠的血糖和胰岛素水平,也具有促进皮层和海马神经元及其突触发生的效应。然而,(D-Ser2)Oxm是否能拮抗AD时Aβ所致的细胞损伤仍缺乏实验依据。本研究在培养原代大鼠海马神经细胞基础上,通过细胞活性和早期凋亡测定、细胞内钙成像以及线粒体膜电位检测,研究了(D-Ser2)Oxm对Aβ1-42所致细胞毒性的拮抗效应。结果显示,与单独给予Aβ1-42处理的细胞相比,(D-Ser2)Oxm+Aβ1-42处理组的细胞活力明显提高,而加入GLP-1受体抑制剂exendin(9-39)后,细胞活力则显著下降;(D-Ser2)Oxm可有效拮抗Aβ1-42导致的细胞凋亡,并使凋亡相关蛋白caspase3含量显著降低;(D-Ser2)Oxm处理还有效阻止了Aβ1-42引起的海马细胞内钙水平升高、线粒体膜电位去极化以及糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)(Y216)的活化。以上结果表明,(D-Ser2)Oxm可能是通过激动GLP-1受体对抗Aβ1-42的神经毒性,并且这种保护效应可能与细胞内钙稳态调节和线粒体膜电位稳定有关。     

抗糖尿病新药(D-Ser2)Oxm拮抗淀粉样β蛋白细胞毒性的神经保护效应观察

淀粉样β蛋白(amyloidβ-protein,Aβ)在脑内的沉积及其神经毒性是阿尔茨海默病(Alzheimer’s disease,AD)的主要原因之一,目前仍缺乏拮抗Aβ的有效药物。最新报道表明,一种新的抗糖尿病药物(D-Ser2)Oxm不仅可以改善2型糖尿病(T2DM)大鼠的血糖和胰岛素水平,也具有促进皮层和海马神经元及其突触发生的效应。然而,(D-Ser2)Oxm是否能拮抗AD时Aβ所致的细胞损伤仍缺乏实验依据。本研究在培养原代大鼠海马神经细胞基础上,通过细胞活性和早期凋亡测定、细胞内钙成像以及线粒体膜电位检测,研究了(D-Ser2)Oxm对Aβ1-42所致细胞毒性的拮抗效应。结果显示,与单独给予Aβ1-42处理的细胞相比,(D-Ser2)Oxm+Aβ1-42处理组的细胞活力明显提高,而加入GLP-1受体抑制剂exendin(9-39)后,细胞活力则显著下降;(D-Ser2)Oxm可有效拮抗Aβ1-42导致的细胞凋亡,并使凋亡相关蛋白caspase3含量显著降低;(D-Ser2)Oxm处理还有效阻止了Aβ1-42引起的海马细胞内钙水平升高、线粒体膜电位去极化以及糖原合成酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)(Y216)的活化。以上结果表明,(D-Ser2)Oxm可能是通过激动GLP-1受体对抗Aβ1-42的神经毒性,并且这种保护效应可能与细胞内钙稳态调节和线粒体膜电位稳定有关。     

海马神经元敲低MCU改善阿尔茨海默病小鼠学习记忆功能障碍

阿尔茨海默病(Alzheimer’s disease, AD)是一种严重威胁老年人健康的神经退行性疾病,目前为止仍然缺乏有效的治疗方法。最新研究表明,线粒体功能紊乱是AD发展的直接原因。线粒体钙离子单向转运体(mitochondrial calcium uniporter,MCU)位于线粒体内膜,是线粒体Ca2+摄取的主要通道。MCU表达异常可引起线粒体钙稳态失衡,最终导致线粒体功能紊乱。本研究旨在明确敲低MCU对AD海马神经元和模型小鼠学习记忆功能的影响。以慢病毒和腺相关病毒为载体转染sh RNA,分别干扰海马神经元(HT22细胞)和淀粉样前体蛋白(amyloid precursor protein, APP)/早老素1 (presenilin 1, PS1)/tau AD转基因小鼠海马MCU表达,用MTS法检测HT22细胞活性,用Y迷宫和Morris水迷宫实验检测APP/PS1/tau转基因小鼠学习记忆功能障碍的变化。结果显示,MCU低表达可以逆转β淀粉样蛋白1-42 (amyloid beta protein 1-42, Aβ1-42)或冈田酸(okadaic acid, OA)...     

Aβ25-35诱导大鼠记忆减退时脑组织损伤及热耐受后HSP70变化对其的影响

目的探讨Aβ25-35诱导模拟人类Alzheimer’s病(AD)的大鼠病理模型中神经元受损与老年性记忆减退之间的关系,以及热耐受处理致HSP70产生对其的影响。方法采用海马内一次性注射β-淀粉样多肽25-35片段(Aβ25-35)制作大鼠AD模型,一周后进行水迷宫行为学测定,采用免疫组化法检测海马CA1区HSP70的表达、HE染色观察细胞形态、流式细胞仪检测神经元的坏死和凋亡。结果与对照组相比,海马内注射Aβ25-35后出现学习记忆能力降低,神经元的坏死和凋亡增多,并且海马区有HSP70的生成,而热休克预处理组能够进一步增加HSP70的生成(P<0·05),减轻神经元的坏死和凋亡的程度(P<0·05)。结论海马内注射Aβ25-35诱导的大鼠学习记忆功能低下与凋亡导致神经元数量减少有关,而Aβ的毒性是神经元凋亡的重要原因,热休克预处理通过增加热休克蛋白表达,对神经元起一定的保护作用。     

骨钙素的中枢调控作用及其生物学机制

骨钙素(OCN)能调节多种外周组织器官的生理结构与功能,也发挥重要的中枢调控作用,与个体的学习和记忆等高级认知功能密切相关。研究表明,OCN穿过血脑屏障进入大脑,并与神经元或神经胶质细胞膜上的G蛋白偶联受体(GPCR)家族成员GPR158和GPR37结合,激活或抑制细胞内相关信号通路,改变神经元或神经胶质细胞的生理活性。OCN在脑内的作用主要包括调节5-羟色胺、多巴胺、去甲肾上腺素和γ-氨基丁酸等神经递质合成与释放、增加脑源性神经营养因子表达、促进海马神经发生、增强海马神经元自噬及维持髓鞘稳态等。此外,OCN还能参与调控多种神经退行性疾病的病理生理学进程。在阿尔茨海默病(AD)中,OCN干预能够部分减少β-淀粉样蛋白(Aβ)沉积及Aβ诱发的细胞毒性等,改善学习和记忆能力缺陷;在帕金森氏病(PD)中,OCN干预能够部分抑制黑质和纹状体多巴胺能神经元丢失,增加酪氨酸羟化酶含量及降低神经炎症等,缓解运动功能障碍。本文通过解析GPR158和GPR37的结构与功能,分析OCN在脑内的作用及其生物学机制,探讨OCN对AD和PD等神经退行性疾病的影响,为进一步筛选促进脑健康的新型靶点提供依据。     

Free Copper,Ferroxidase and SOD1 Activities,Lipid Peroxidation and NO<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript> Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases

The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.     

Neurodegenerative Diseases: Pathology and the Advantage of Single-Cell Profiling

The aggregation of neuronal proteins as inclusions is emerging as a common mechanistic theme in neurodegenerative diseases. The presence of these "disease-specific" pathologic changes in the brains of patients with neurodegenerative diseases assist pathologists in the diagnosis and characterization of dementing illnesses. However, these same inclusions may provide valuable clues toward understanding common pathologic roots and shared abnormalities in protein folding across disorders. Such an investigation will likely provide insights into disease mechanisms underlying neurodegenerative disorders characterized by abundant filamentous lesions. This review focuses on two themes: (i) Neurodegenerative disorders are characterized by shared and distinct histopathological and biochemical abnormalities, and (ii) the presence of abnormal protein aggregates may alter a gene, and hence protein expression in inclusion-bearing neurons predisposes them to dysfunction and eventual neuronal degeneration. The pathologic features of neurodegenerative diseases are first discussed followed by a rationale behind sampling mRNA species from single cells rather than from whole-brain homogenates to explore disease mechanisms.     

Proteins and mutations: a new vision (molecular) of neurodegenerative diseases

Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.     

溶酶体离子通道蛋白在神经退行性疾病发生发展中的作用及机制研究

溶酶体离子通道蛋白异常引起溶酶体功能障碍是导致阿尔茨海默病(Alzheimer’s disease,AD)和帕金森病(Parkinson’s disease,PD)等神经退行性疾病的重要因素.溶酶体离子通道蛋白调节溶酶体内离子稳态、溶酶体膜电压以及溶酶体的酸度.溶酶体离子通道蛋白的结构或功能缺陷会引起溶酶体降解功能障碍,导致神经退行性疾病的发生发展.在这篇综述中,我们总结了各种离子通道蛋白调节溶酶体功能的过程及机制,以及离子通道蛋白异常参与神经退行性疾病的过程和机制.调节离子通道蛋白改善溶酶体的功能、促进异常聚集蛋白的清除,是神经退行性疾病治疗的潜在途径.     

Modelling neurodegenerative diseases with 3D brain organoids

Neurodegenerative diseases are incurable and debilitating conditions characterized by the deterioration of brain function. Most brain disease models rely on human post‐mortem brain tissue, non‐human primate tissue, or in vitro two‐dimensional (2D) experiments. Resource limitations and the complexity of the human brain are some of the reasons that make suitable human neurodegenerative disease models inaccessible. However, recently developed three‐dimensional (3D) brain organoids derived from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs, may provide suitable models for the study of the pathological features of neurodegenerative diseases. In this review, we provide an overview of existing 3D brain organoid models and discuss recent advances in organoid technology that have increased our understanding of brain development. Moreover, we explain how 3D organoid models recapitulate aspects of specific neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and explore the utility of these models, for therapeutic applications.     

Protein misfolding in the late‐onset neurodegenerative diseases: Common themes and the unique case of amyotrophic lateral sclerosis

Enormous strides have been made in the last 100 years to extend human life expectancy and to combat the major infectious diseases. Today, the major challenges for medical science are age‐related diseases, including cancer, heart disease, lung disease, renal disease, and late‐onset neurodegenerative disease. Of these, only the neurodegenerative diseases represent a class of disease so poorly understood that no general strategies for prevention or treatment exist. These diseases, which include Alzheimer's disease, Parkinson's disease, Huntington's disease, the transmissible spongiform encephalopathies, and amyotrophic lateral sclerosis (ALS), are generally fatal and incurable. The first section of this review summarizes the diversity and common features of the late‐onset neurodegenerative diseases, with a particular focus on protein misfolding and aggregation—a recurring theme in the molecular pathology. The second section focuses on the particular case of ALS, a late‐onset neurodegenerative disease characterized by the death of central nervous system motor neurons, leading to paralysis and patient death. Of the 10% of ALS cases that show familial inheritance (familial ALS), the largest subset is caused by mutations in the SOD1 gene, encoding the Cu, Zn superoxide dismutase (SOD1). The unusual kinetic stability of SOD1 has provided a unique opportunity for detailed structural characterization of conformational states potentially involved in SOD1‐associated ALS. This review discusses past studies exploring the stability, folding, and misfolding behavior of SOD1, as well as the therapeutic possibilities of using detailed knowledge of misfolding pathways to target the molecular mechanisms underlying ALS and other neurodegenerative diseases. Proteins 2013; 81:1285–1303. © 2013 Wiley Periodicals, Inc.     

Induced pluripotent stem cells (iPSCs) as game-changing tools in the treatment of neurodegenerative disease: Mirage or reality?

Based on investigations, there exist tight correlations between neurodegenerative diseases' incidence and progression and aberrant protein aggregreferates in nervous tissue. However, the pathology of these diseases is not well known, leading to an inability to find an appropriate therapeutic approach to delay occurrence or slow many neurodegenerative diseases' development. The accessibility of induced pluripotent stem cells (iPSCs) in mimicking the phenotypes of various late-onset neurodegenerative diseases presents a novel strategy for in vitro disease modeling. The iPSCs provide a valuable and well-identified resource to clarify neurodegenerative disease mechanisms, as well as prepare a promising human stem cell platform for drug screening. Undoubtedly, neurodegenerative disease modeling using iPSCs has established innovative opportunities for both mechanistic types of research and recognition of novel disease treatments. Most important, the iPSCs have been considered as a novel autologous cell origin for cell-based therapy of neurodegenerative diseases following differentiation to varied types of neural lineage cells (e.g. GABAergic neurons, dopamine neurons, cortical neurons, and motor neurons). In this review, we summarize iPSC-based disease modeling in neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease. Moreover, we discuss the efficacy of cell-replacement therapies for neurodegenerative disease.     

The alpha-ketoglutarate dehydrogenase complex in neurodegeneration

Altered energy metabolism is characteristic of many neurodegenerative disorders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglutarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerative disorders including Alzheimer's Disease (AD). The reductions in KGDHC activity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, including the actions of free radicals (Reactive Oxygen Species, ROS). Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases. Reductions in KGDHC activity can be plausibly linked to several aspects of brain dysfunction and neuropathology in a number of neurodegenerative diseases. Further studies are needed to assess mechanisms underlying the sensitivity of KGDHC to oxidative stress and the relation of KGDHC deficiency to selective vulnerability in neurodegenerative diseases.     

The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer's and Parkinson's diseases

Alzheimer's (AD) and Parkinson's diseases (PD) are late-onset neurodegenerative diseases that have tremendous impact on the lives of affected individuals, their families, and society as a whole. Remarkable efforts are being made to elucidate the dominant factors that result in the pathogenesis of these disorders. Extensive postmortem studies suggest that oxidative/nitrative stresses are prominent features of these diseases, and several animal models support this notion. Furthermore, it is likely that protein modifications resulting from oxidative/nitrative damage contribute to the formation of intracytoplasmic inclusions characteristic of each disease. The frequent presentation of both AD and PD in individuals and the co-occurrence of inclusions characteristic of AD and PD in several other neurodegenerative diseases suggests the involvement of a common underlying aberrant process. It can be surmised that oxidative/nitrative stress, which is cooperatively influenced by environmental factors, genetic predisposition, and senescence, may be a link between these disorders.     

The role of mitochondria in inherited neurodegenerative diseases

In the past decade, the genetic causes underlying familial forms of many neurodegenerative disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich ataxia, hereditary spastic paraplegia, dominant optic atrophy, Charcot-Marie-Tooth type 2A, neuropathy ataxia and retinitis pigmentosa, and Leber's hereditary optic atrophy have been elucidated. However, the common pathogenic mechanisms of neuronal death are still largely unknown. Recently, mitochondrial dysfunction has emerged as a potential 'lowest common denominator' linking these disorders. In this review, we discuss the body of evidence supporting the role of mitochondria in the pathogenesis of hereditary neurodegenerative diseases. We summarize the principal features of genetic diseases caused by abnormalities of mitochondrial proteins encoded by the mitochondrial or the nuclear genomes. We then address genetic diseases where mutant proteins are localized in multiple cell compartments, including mitochondria and where mitochondrial defects are likely to be directly caused by the mutant proteins. Finally, we describe examples of neurodegenerative disorders where mitochondrial dysfunction may be 'secondary' and probably concomitant with degenerative events in other cell organelles, but may still play an important role in the neuronal decay. Understanding the contribution of mitochondrial dysfunction to neurodegeneration and its pathophysiological basis will significantly impact our ability to develop more effective therapies for neurodegenerative diseases.