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1、基底神经节疾病基底神经节疾病 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 functionSt
2、ructureConnections 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.internal globus pallidus(GPi)external globus pallidus(GPe)ConnectionsGlutamateGABA Dopamine Direct:Motor cort
3、ex Putamen GPi Thalamus Motor cortex Indirect:Motor cortex Putamen GPe Subthalamic nucleus GPi Thalamus Motor cortexNigrostriatal pathway:Pars compacta StriatumGluGABAGABAGluGluGABAGABAGluGABAGluParkinsons disease，PDAn Essay on the Shaking Palsy English physician James Parkinson(1817)IntroductionPD
4、is the most common neurodegenerative disorder after Alzheimers disease.Monograph by James Parkinson1817SymptomatologyMovement disorders:resting tremor muscle rigiditybradykinesia and postural instability ParkinsonismCognitive and neurobehavioral problems(dementia)Sensory and sleep difficulties chron
5、ic and progressiveThe relationship of the basal ganglia to the major components of the motor system.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 Basal GangliaGeneticDopamine oxidative stressToxinsOthersCircuit disorder of Basal Ga
6、ngliainhibition of the direct pathwayexcitation of the indirect pathway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+O2O2H2O2多巴胺半醌多巴胺半醌多巴胺醌多巴胺醌DAO2MAODOPACH2O2HVACOMTDopamine oxidative stressDopamine oxidative stressToxinsRotenone(an insecticide)MPTP 1-methyl-4-phenyl-1,2,3,6-tetra
7、hydropyridine（1-甲基-4-苯基-1,2,3,6-四氢吡啶）Paraquat(a herbicide)6-Hydroxydopamine(6-OHDA)Heavy metals MPTPParaquatThe neurotoxins used in animal models of PD induce mitochondrial dysfunction.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
8、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 presynaptic terminals include,and -synuclein play a role in synaptic vesicle recycling,storage and compartmentalization of neurotransm
9、itters and associates with vesicular and membranous structuresSer129的磷酸化-synuclein基因的倍增 Overview of the a-syn aggregation process integrated with the oxidative stress pathway and the UPP.Parkin functions as an E3 ubiquitin protein ligase by targeting misfolded proteins to the ubiquitn proteasome pat
10、hway 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 3.PINK1(PTEN-induced putative kinase 1)/PARK6serinethreonine kinase(mitochondria)a pivotal regulator of mitochondrial quality4.UCH-L1/
11、PARK5utative kinase 1(PINK1)Ubiquitin carboxyl-terminal hydrolase L1neuron-specific protein PGP 9.5one of the most abundant proteins in the brain(2%)hydrolytic activity,ligase activity and binding mono-ubPossible role of UCH-L1 in PD.Mechanisms of neurotoxicant-induced proteasome dysfunction and dop
12、aminergic degeneration.Transgenic animal model alpha-synuclein A30P+A53T,LRRK2(R1441G),parkin,R621C synphilin-1 mouse,C.elegans,Drosophila,zebrafish InflammationNeuroinflammation is mediated predominately by microglia,the resident immuno-competent and phagocytic cells within the CNS.Microglia,repres
13、enting 520%of brain cellsMicroglial cell density in the SN is 45 times higher than in other regionsActivated cells also produce pro-inflammatory moleculesSchematicrepresentationoflipopolysaccharide(LPS)-inducedandglialactivation-mediateddopamine(DA)neurodegeneration.Key molecular mechanisms that are
14、 widely accepted to contribute to the neurodegenerative process in dopaminergic neurons in the substantia nigra in Parkinson disease.At least two of the three major symptoms are present.Possible causes for symptoms Response to levodopa The main tools used to make a diagnosis:Neurological examination
15、 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 symptoms.Medications control symptoms primarily by controlling the imbalance between the tran
16、smitters.Therapeutic strategyDirectly improve the function of dopamine neurotransmission Indirectly improve the function of dopamineSurgery and deep brain stimulationdopamine in the brain Precursor Rate-limiting step,decrease in PDL-dopaPeripheral inhibitorsThe central and peripheral metabolism of l
17、evodopa 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 variety of side effects COMT inhibitors,MAO-B inhibitorsL-dopaLong-term effects of L-DOPA：On/off oscilla
18、tions Dose failure(drug resistance)Dopamine dysregulation syndromeAch:movementAch increases inhibition o GABAdenosine:movementAdenosine increase the effects of Ach on the GABAergic neurons;Adenosine counter D2 receptor activity;Adenosine reduces GABA release.Enkephalin DynorphinPeptide modulation of
19、 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 cause permanent destruction of brain tissue,they have largely been replaced by deep brain stimulation(DBS)for treatm
20、ent 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 Gene therapy(virus)Neuroprotective treatments(GDNF)Neural transplantation Stem cells transplants have raised great rec
21、ent 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 manipulate their use is controversial.Such controversy may be overcome with the use of induced pluripotent stem cells from ad
22、ults.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 vectors.Red cells indicate the cells expressing the exogenous genes.(3)Harvest and culture the cells according to ES cell culture,u
23、sing mitotically inactivated feeder cells(lightgray).(4)A small subset of the transfected cells become iPS cells and generate ES-like colonies.主要讲解的内容主要讲解的内容:1基底神经节的脑内组成的核团、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：1
24、Whatarethecomponentsofthebasalganglia?2Howarethestructuresofthebasalgangliaconnected?3Describethecorticostriatalprojections.4Describetheconnectionsbetweensubthalamusandglobuspallidus.5Describetheimportanceofthenigrastritalpathways.6Whatistheroleofthebasalgangliainrelationtothemotorthalamus?7Whataret
25、heprincipalneurotransmittersandreceptorsassociatedwiththebasalganglia?8Adisorderofthebasalgangliaisindicatedwhatsigns?9CanadministrationofdopaminecureParkinsonsdisease?Why?10.DescribetheetiologyofneurodegenerationinthesubstantianigrainPD.11.WhydoselesioningtheSThnorGPreducethesymptomsofPD?Huntington
26、s disease(HD)In 1872 George Huntington thoroughly described the disorder in 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）progres
27、sive neurodegenerative disorder,which affects muscle coordination and 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 s
28、triatum.astrocytesPathologynuclear and cytoplasmic inclusionsPathogenesisPathogenesisHtt is expressed in all mammalian cells.(brain)interacts with over 100 other proteins,and appears to have multiple biological functions.embryonic development,anti-apoptosis,controling the production of BDNF,facilita
29、ting vesicular transport and synaptic transmission,and controling neuronal gene transcription.Pathogenesis1.Loss of Htt function 2.Toxic function of mHttGlutamateGABA Dopamine Diagnosis typical symptoms a family history of the disease genetic testing to have the expanded trinucleotide repeatphysical
30、 examination,psychological examination,Medical imaging There is no known cure for HD.Treatment is aimed at controlling the symptoms.tetrabenazine(chorea)antipsychotic drugs TreatmentPrognosis The length of the trinucleotide repeat accounts for 60%of the variation in the age of onset and the rate of
31、progression of symptoms.A longer repeat results in an earlier age of onset and a faster progression of symptoms.Life expectancy in HD is generally around 20years following the onset of visible symptoms.Research directions Appropriate animal models(transgenic animals)Genetically engineered intrabodies(an inhibition of mHtt aggregation)have been shown to prevent mortality during the development stages of Drosophila models.Gene silencing(mHtt is reduced)Stem cell therapy Numerous drugs Thank you！