神经生物学：基底神经节疾病

1、基底神经节疾病Disease of the Basal GangliaOutline1.Introduction of basal ganglia Overview and function, structure, and connections2.Disorders of basal ganglia Parkinsons disease Huntingtons disease (symptomatology, pathology, pothogenesis, treatment)1.Introduction of basal gangliaOverview and functionStruc

2、tureConnections The basal ganglia are a group of nuclei in the brain interconnected with the cerebral cortex, thalamus and brainstem. Functions: motor control, cognition, emotions, and learning. 锥体系统internal globus pallidus (GPi)external globus pallidus (GPe) ConnectionsCircuit of Basal GangliaDirec

3、t pathwayIndirect pathwayNigrostriatal pathwayGlutamateGABA Dopamine Direct: Motor cortex Putamen GPi Thalamus Motor cortex Indirect: Motor cortex Putamen GPe Subthalamic nucleus GPi Thalamus Motor cortexNigrostriatal pathway: Pars compacta StriatumGluGABAGABAGluGluGABAGABAGluGABAGlu2. Disorders of

4、Basal Ganglia Diminished movement: Parkinsons diseaseExcessive movement: Huntington diseaseNeuropsychiatric cognitive and behavioral disturbancesParkinsons disease，PDAn Essay on the Shaking Palsy English physician James Parkinson (1817) IntroductionPD is the most common neurodegenerative disorder af

5、ter Alzheimers disease.The prevalence is 0.3 in the whole population in industrialized countries, rising to 1% in those over 60 years of age and to 4% of the population over 80. Mean age of onset is around 60 years, although 5-10% of cases are considered of young onset ( the age of 20 and 50). The i

6、ncidence is between 8 and 18 per 100.000 person-years. EpidemiologyMonograph by James Parkinson1817SymptomatologyMovement disorders: resting tremor muscle rigiditybradykinesia and postural instability ParkinsonismCognitive and neurobehavioral problems(dementia)Sensory and sleep difficulties chronic

7、and progressiveThe relationship of the basal ganglia to the major components of the motor system. Origins and terminations of (a) the corticospinal tract and (b) the rubrospinal tract.正常年青人，黑质细胞数为42.5万正常80岁老人，黑质细胞数减少到20.0万PD病人黑质细胞数减少到少于10 .0万Lewy bodyPathologyEtiologyPathogenesisCircuit disorder of

8、Basal GangliaGeneticDopamine oxidative stressToxinsOthersCircuit disorder of Basal Gangliainhibition of the direct pathwayexcitation of the indirect pathway多巴胺神经元为何会发生黑质部选择性的退行性变呢？氧化应激损伤1、外源性毒物的侵入2、神经黑色素的存在3、DA的氧化应激代谢4、清除自由基的能力不全图31-5 多巴胺在神经元中的酶代谢及其代谢产物引自金国章,脑内多巴胺的生物医学1998年 Fe2+Fe3+O2O2Fe2+Fe3+O2O2H

9、2O2多巴胺半醌多巴胺醌DAO2MAODOPACH2O2HVACOMT Dopamine oxidative stressDopamine oxidative stressToxinsRotenone (an insecticide)MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（1-甲基- 4-苯基- 1, 2, 3, 6-四氢吡啶）Paraquat (a herbicide) 6-Hydroxydopamine ( 6-OHDA) Heavy metals RotenoneMPTPParaquat6-Hydroxydopamine, or

10、 6-OHDA 一种理想的动物模型应该符合下列5种标准：1. 出生时，应有正常而完整的DA neurons，并在成年期开始逐渐退化丧失且超过50%。2. 具有容易检测的运动功能障碍。3. Lewy bodies的形成。4. 如模式是genetic，应以单一点突变为基础。5. 较短的时程，约数月。Geneticmitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation 1.Synuclein (SNCA)/PARK1seen mainly in pre

11、synaptic terminals include , and -synuclein play a role in synaptic vesicle recycling, storage and compartmentalization of neurotransmitters and associates with vesicular and membranous structuresSer129的磷酸化 -synuclein基因的倍增 Figure 1 Histological and immunocytochemical analysis of a-synuclein transgen

12、ic files.HETHDDC -synuclein -synuclein -synucleinFigure 2 Electron microscopy of a-synuclein inclusions Figure 3 Premature loss of climbing ability in a-synuclein transgenic files.Figure 4 Retinal degeneration in a-synuclein transgenic files.Parkin functions as an E3 ubiquitin protein ligase by targ

13、eting misfolded proteins to the ubiquitn proteasome pathway for degradation, and the loss of its E3 ligase activity due to mutations lead to autosomal recessive early-onset PD. 2.Parkin/PARK2ubiquitin proteasome system，UPS Figure 1 parkin mRNA expression in developing embryos,adult tissues and parki

14、n knockdown embryos.Figure 2 parkin knockdown results in specific mitochondrialcomplex I deficiency.Figure 3 Knockdown of parkin via MO injection decreasesdiencephalic dopaminergic neuron count.Figure 4 Knockdown of parkin via MO injection is specific to dopaminergic neurons.Figure 5 Swimming behavi

15、our Figure 6 Gross mitochondrial morphologyFigure 7 Electron-dense staining in t-tubules of parkin knockdown embryos.Transgenic animal model alpha-synuclein A30P+A53T, LRRK2(R1441G), parkin, R621C synphilin-1 mouse, C. elegans , Drosophila, zebrafish InflammationNeuroinflammation is mediated predomi

16、nately by microglia, the resident immuno-competent and phagocytic cells within the CNS.Microglia, representing 520% of brain cellsMicroglial cell density in the SN is 45 times higher than in other regionsActivated cells also produce pro-inflammatory moleculesFig. Schematic representation of lipopoly

17、saccharide(LPS)-induced and glial activation-mediated dopamine (DA) neurodegeneration. Pathogenic mechanisms have been suggested, including oxidative stress, mitochondrial defects, protein mishandling and inflammation.At least two of the three major symptoms are present.Possible causes for symptoms

18、Response to levodopa The main tools used to make a diagnosis: Neurological examination Motor physiology tests Neuro-imaging: PET(18-flurodopa ),CT, MRI Lewy bodies during autopsy (gold standard) DiagnosisTreatment There is no known cure for Parkinsons disease. Treatment is aimed at controlling the s

19、ymptoms. Medications control symptoms primarily by controlling the imbalance between the transmitters.Therapeutic strategyDirectly improve the function of dopamine neurotransmission Indirectly improve the function of dopamineSurgery and deep brain stimulationdopamine in the brain Precursor Rate-limi

20、ting step , decrease in PDL-dopaPeripheral inhibitorsFig. The central and peripheral metabolism of levodopa and its modification by drugs.easily pass through the blood-brain barrieris transformed into dopamine in the dopaminergic neurons by DDCis often metabolised to DA elsewhere, causing a wide var

21、iety of side effects COMT inhibitors , MAO-B inhibitorsL-dopaLong-term effects of L-DOPA： On/off oscillations Dose failure (drug resistance)Dopamine dysregulation syndromeAch: movementAch increases inhibition o GABAdenosine: movementAdenosine increase the effects of Ach on the GABAergic neurons;Aden

22、osine counter D2 receptor activity;Adenosine reduces GABA release.Enkephalin DynorphinFig. Peptide modulation of striatal input to the globus pollidus.Pallidotomy and Subthalamotomy Surgery is used in people with advanced PD for whom drug therapy is no longer sufficient.Because these procedures caus

23、e permanent destruction of brain tissue, they have largely been replaced by deep brain stimulation (DBS) for treatment of Parkinsons disease.DBS is primarily used to stimulate one of three brain regions: the subthalamic nucleus, the globus pallidus, or the thalamus.Research directions Animal models

24、Gene therapy (virus )Neuroprotective treatments (GDNF)Neural transplantation Stem cells transplants have raised great recent interest. When transplanted into the brains of rodents and monkeys they survive and improve behavioral abnormalities. Nevertheless while fetal stem cells are the easiest to ma

25、nipulate their use is controversial. Such controversy may be overcome with the use of induced pluripotent stem cells from adults. A scheme of the generation of induced pluripotent stem (iPS) cells. (1)Isolate and culture donor cells. (2)Transfect stem cell-associated genes into the cells by viral ve

26、ctors. Red cells indicate the cells expressing the exogenous genes. (3)Harvest and culture the cells according to ES cell culture, using mitotically inactivated feeder cells (lightgray). (4)A small subset of the transfected cells become iPS cells and generate ES-like colonies. 主要讲解的内容:1基底神经节的脑内组成的核团

27、、它们的分布、主要通路的组成 及其参与调节每条通路中的神经递质及其功能。2基底神经节（黑质）损伤后的主要临床表现及其病理表现的关系。3 PD脑内黑质多巴胺神经元退化的机制研究。4 Parkinsons Disease (PD)的治疗方案及治疗基础。思考题：1What are the components of the basal ganglia?2How are the structures of the basal ganglia connected?3Describe the corticostriatal projections.4Describe the connections bet

28、ween subthalamus and globus pallidus.5Describe the importance of the nigrastrital pathways.6What is the role of the basal ganglia in relation to the motor thalamus?7What are the principal neurotransmitters and receptors associated with the basal ganglia?8A disorder of the basal ganglia is indicated

29、what signs?9Can administration of dopamine cure Parkinsons disease? Why?10. Describe the etiology of neurodegeneration in the substantia nigra in PD.11. Why dose lesioning the SThn or GP reduce the symptoms of PD?Huntingtons disease (HD)In 1872 George Huntington thoroughly described the disorder in

30、his first paper On Chorea .IntroductionThe worldwide prevalence of HD is 5-10 cases per 100,000 persons. It usually appears in middle age (30-50 years)EpidemiologyHD/chorea is an inherited （ autosomal dominant inheritance ）progressive neurodegenerative disorder, which affects muscle coordination and

31、 leads to cognitive decline and dementia. It typically becomes noticeable in middle age.abnormalities in peripheral tissues ( muscle atrophy, cardiac failure, impaired glucose tolerance)SymptomatologyProminent cell loss and atrophy in striatum.astrocytesPathologynuclear and cytoplasmic inclusionsPat

32、hogenesisPathogenesisHtt is expressed in all mammalian cells. ( brain and testes) interacts with over 100 other proteins, and appears to have multiple biological functions.embryonic development, anti-apoptosis, controling the production of BDNF, facilitating vesicular transport and synaptic transmission