神經(jīng)退行性疾病的分子病理學(xué)研究進(jìn)展教學(xué)課件

1、神經(jīng)退行性疾病分子病理學(xué)研究進(jìn)展課程提綱神經(jīng)退行性疾病的病理變化神經(jīng)退行性疾病的致病因素及其機(jī)制神經(jīng)退行性疾病的研究進(jìn)展神經(jīng)退行性疾病 神經(jīng)退行性疾?。╪eurodegenerative diseases）是一類慢性、隨著年齡增長(zhǎng)而進(jìn)行性加重的神經(jīng)系統(tǒng)疾病，由神經(jīng)退行性病變而引起。Neurodegeneration is the term for the progressive loss of structure or function of neurons, including death of neurons.常見神經(jīng)退行性疾病Nat Rev Neurosci 2003, 4:49-60P

2、rotein deposition in the brain of different types of neurodegenerative diseasesCerebral aggregates in neurodegenerative diseasesNat Rev Neurosci 2003, 4:49-60Extracellular amyloid plaques (white arrows) and intracytoplasmic neurofibrillary tangles (yellow arrows) are the pathological signature of Al

3、zheimers disease. Intracytoplasmic aggregates are typically present in the neurons of people affected by Parkinsons disease and amyotrophic lateral sclerosis. Intranuclearinclusions of huntingtin are observed in Huntingtons disease patients and extracellular prion amyloid plaques that are located in

4、 different brain regions are present in some cases of transmissible spongiform encephalopathy. In spite of the different protein compositions, the ultrastructure of these deposits seems to be similar and composed mainly of a network of fibrillar polymers (centre).神經(jīng)退行性疾?。旱鞍踪|(zhì)異常聚集Nat Rev Neurosci 2003

5、, 4:49-60Abnormal Accumulation of Proteins in the Brain Is Dependent on Their Production and ClearanceCold Spring Harb Perspect Med 2012, 2(6):a006379ADP: A-degrading protease UPS AutophagySelkoe et al, 2001Amyloid Precursor Protein (APP) and Its Processing基因突變或過表達(dá)可導(dǎo)致相關(guān)蛋白生成增加基因突變或過表達(dá)可導(dǎo)致相關(guān)蛋白生成增加Selko

6、e et al, 2001Amyloid Precursor Protein (APP) and Its Processing蛋白質(zhì)錯(cuò)誤折疊與異常聚集Nat Rev Neurosci 2003, 4:49-60蛋白質(zhì)折疊異常影響蛋白質(zhì)的降解和清除Soluble misfolded monomers anddimers can be recognized by both the UPS or CMA(chaperone-mediated autophagy)-related chaperones, and subsequently degraded by eitherof these two p

7、athways. In the case of CMA, cytosolic proteins (i.e., a-synuclein) are recognized by a chaperone (i.e., Hsc70), which delivers the target protein to the lysosome via a receptor protein present in the lysosomal membrane. However, on more complex assembly (oligomer or fibril formation) of the target

8、protein, macroautophagy is the only mechanism available to clear the more insoluble and highly ordered aggregates.Ubiquitin-Proteasome ProteolysisUbiquitin is first activated by the ubiquitin-activating enzyme E1 (A), an ubiquitin-carrier protein, E2, and ATP. The product of this reaction is a high-

9、energy E2 ubiquitin thiol ester intermediate (B). Protein substrates are then ubiquitinated by either binding of the substrate to a specific ubiquitin-protein ligase (E3), and then the E2-bound activated ubiquitin is transferred directly to the E3-bound protein substrate. Or alternatively, the activ

10、ated ubiquitin can be transferred from the E2 to the E3, prior to its conjugation to the E3-bound substrate (C). Following conjugation of the first ubiquitin molecule to the protein substrate, additional ubiquitin molecules can be added to the internal lysine residues of ubiquitin to form a polyubiq

11、uitin chain on the substrate (D). The ubiquitinated substrate is then recognized and degraded by the 26S proteasome complex, leading to the release of short peptides (E). Ubiquitin is recycled via the activity of deubiquitinating enzymes.Autophagy Autophagy is the basic catabolic mechanism that invo

12、lves cell degradation of unnecessary or dysfunctional cellular components through the lysosomal machineryHuntingtons disease: Huntingtin proteininherited autosomal dominant disordermotor impairment, personality changespolyglutamine repeat in the Huntingtin protein of some people causes self associat

13、ion of the protein in nerve cellsintranuclear inclusions killing nerve cellsPolyglutamine (PolyQ) Repeat36 repeats in HDHuntingtons disease: Huntingtin protein舞蹈癥Parkinsons disease: alpha-synucleinLewy bodies form in brain cellsKill cells in part of brain (midbrain) that produces dopamineLess dopami

14、ne means motor control lossLewy BodyAlpha-synucleinThe Lewy body is the pathological hallmark of Parkinson disease. Classical Lewy bodies are often found in the cytoplasm of affected pigmented neurons of the substantia nigra. The Lewy body inclusion shows an eosinophilic core surrounded by a pale ha

15、lo (arrow). The protein alpha-synuclein is a component of the Lewy body.Neuronal loss in Parkinsons disease中腦切片ALS: amyotrophic lateral sclerosisAmytrophic lateral sclerosis. ALS is a progressive fatal disease caused by degeneration of lower motor neurons in the lateral horn of the spinal cord and u

16、pper motor neurons of the cerebral cortex, resulting in progressive motor weakness.Superoxide dismutase(SOD1)/TDP-43/C9ORF72Superoxide dismutase 1 (SOD1)Nature Reviews Neuroscience 2013，14, 248-264 PrPcPrPscsoluble + -enzyme digesting + -polypeptide chain-helical segment-sheetPrion proteinThe native

17、 state (endogenous cellular prion protein, PrPC ) is water-soluble, presenting in healthy cells, with possible function in transmembrane transport or signaling;The other conformational state (misfolded, disease-associated PrPSc (Sc meaning scrapie-associated) is very poorly water-soluble and readily

18、 forms protein aggregates.Prion protein immunoreactivity (purple) and spongiform degeneration in the neocortex of a patient who had died of Creutzfeldt-Jakob disease (CJD)動(dòng)物prion病 人類prion病 羊瘙癢病(scrapie of sheep and goat) 庫(kù)魯病(Kuru disease) 水貂傳染性腦病(transmissible mink encephalopathy,TMM) 克-雅病(Creutzfel

19、d-Jakob disease, CJD) 鹿慢性退行性變(chronic wasting disease of deer, CWD) 格斯特曼綜合征(Grestmann-Straussler Syndrome,GSS) 牛海綿狀腦病(bovine spongiform encephalopathy, BSE) 致死性家庭失眠癥(fatal familial insomnia,FFI) 貓海綿狀腦病(feline spongiform encephalopathy, FSE) 克-雅病變種(variant CJD, v-CJD) Prion-associated Diseases in Hum

20、an and Other AnimalsAlzheimers disease Plaques(Amyloid :A42)NFT(Tau, p-Tau)Extracellular amyloid plaques;Intracellular neurofibrillary tangles (NFT)A deposits in mouse models of AD課程提綱神經(jīng)退行性疾病的病理變化神經(jīng)退行性疾病的致病因素及其機(jī)制神經(jīng)退行性疾病的研究進(jìn)展神經(jīng)退行性疾病的致病因素及其機(jī)制年齡基因突變或過表達(dá)環(huán)境毒素未知因素The Genetics of Alzheimers DiseaseModified

21、 from Tanzi and Bertram, Cell, 2005Key Genomic Discoveries in PDThe Genetics of ALSNature Reviews Neuroscience 14, 248-264 (April 2013)The Genetics of ALSNature Reviews Neuroscience 14, 248-264 (April 2013)Environmental toxin hypothesis(以PD為例) MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine): a n

22、eurotoxin precursor to MPP+, which causes permanent symptoms of Parkinsons disease by destroying dopaminergic neurons in the substantia nigra of the brain. Rotenone: pesticide 魚藤酮 Paraquat: herbicide 百草枯 Maneb: fungicide 代森錳 Toxicity of MPTP in MiceNature Protocols, 2007致病途徑蛋白質(zhì)錯(cuò)誤折疊和聚集線粒體功能異常氧化應(yīng)激炎癥反應(yīng)

23、Models for the Toxic Mechanism ofMisfolded AggregatesAt least four hypotheses have been proposed to explain the mechanism of neurotoxicity associated with protein misfolding and aggregation: activation of an apoptotic signalling pathwayrecruitment of essential cellular factorsformation of ion channe

24、lsthe induction of oxidative stress.aggregatesNat Rev Neurosci 2003, 4:49-60Models for the Mechanism of Cellular Toxicity associated with Protein Misfolding and AggregationNat Rev Neurosci 2003, 4:49-60DiseasesMechanisms of actions of various toxins in PDTIPS, 2009, 30:475-483Schematic Representatio

25、n of Mitochondrial CompartmentalizationImmune Contributions to PD Pathogenesis課程提綱神經(jīng)退行性疾病的病理變化神經(jīng)退行性疾病的致病因素及其機(jī)制神經(jīng)退行性疾病的研究進(jìn)展Soluble oligomers are more toxicNat Rev Neurosci 2003, 4:49-60-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015 Aug 31A new site for APP pr

26、ocessingNat Neurosci. 2015 Sep 9. doi: 10.1038/nn.4117.Transmission of Neurodegenerative Diseases: A Common Mechanism for Pathogenesis？Nat Neurosci. 2015 Sep 9. doi: 10.1038/nn.4117.Neurodegeneration: Amyloid- pathology induced in humansNature. 2015 Sep 10;525(7568):247-50Nature. 2015 Sep 10;525(756

27、8):193-4.Summary of evidence supporting the propagation and transmission of non-prion neurodegenerative disease proteinsNature Reviews Neuroscience 16, 109120 (2015) The prion paradigm of seeded protein aggregationTau post-translational modifications Nat Neurosci. 2015 Aug;18(8):1183-9. Tau Acetylat

28、ion and ADNature CommunicationsCritical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015，21(10):1154-1162Circuits or Network Mechanisms of Neurodegenerative DisordersAberrant Neural Network Activity May Cause Cognitive Dysfunction in ADPalop J, Nat Neurosci

29、 2010Immune attack: the role of inflammation in neurodegenerative diseasesNature Reviews Neuroscience 16, 358372 (2015)Summary相關(guān)蛋白的過度聚集可導(dǎo)致神經(jīng)退行性疾病基因突變或環(huán)境因素可導(dǎo)致蛋白質(zhì)錯(cuò)誤折疊，從而引起蛋白質(zhì)過度聚集蛋白質(zhì)異常折疊及其聚集可導(dǎo)致神經(jīng)元死亡或功能障礙線粒體功能異常、氧化應(yīng)激、炎癥反應(yīng)等在神經(jīng)退行性疾病中起重要作用Further Reading-Synuclein strains cause distinct synucleinopathies a

30、fter local and systemic administration. Nature. 2015 Jun 18;522(7556):340-4. -Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015 Aug 31The changing scene of amyotrophic lateral sclerosis Nature Reviews Neuroscience 14, 248-264 (April 2013)Critical role of acetyla

31、tion in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015 Sep 21Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci. 2015 Aug;18(8):1183-9. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neu

32、ron. 2010 Sep 23;67(6):953-66.Evidence for human transmission of amyloid- pathology and cerebral amyloid angiopathy. Nature. 2015 Sep 10;525(7568):247-50.Persistence of A seeds in APP null mouse brain. Nat Neurosci. 2015 Sep 9;GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transpor

33、t. Nature. 2015 Sep 3;525(7567):129-33. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61.Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015 Aug 26;18(9):1226-9. Luk, K. C. et a

34、l. Pathological -synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949953 (2012). DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245256 (2011).Re

35、nton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257268 (2011). Spreading of pathology in neurodegenerative disease: a focus on human studies. Nature Reviews Neuroscience 16, 109120.Further Reading思 考 題名詞解釋：神經(jīng)退行性疾病簡(jiǎn)答題： 以阿爾茨海默病

36、為例，簡(jiǎn)述神經(jīng)退行性疾病中 相關(guān)蛋白異常聚集的原因。 簡(jiǎn)述蛋白質(zhì)異常聚集引起神經(jīng)退行性病變的機(jī) 理。Two Pathways toAggregation.A peptides form either small, type 1 oligomers, which stray into synapses and disrupt memory, or large, stable aggregates, which clump into plaques. Plaques then give rise to local, fibril-like type 2 oligomers. Image court

37、esy of Cell Reports, Liu etal.Aggregates of the phosphorylated microtubule-associated protein tau in neurofibrillary tangles and neuropil threads, together with deposits of amyloid- (A), are characteristic of sporadic Alzheimer disease (AD). Tau pathology alone also characterizes a subgroup of cases

38、 of frontotemporal lobar degeneration (FTLD), which is designated as FTLD-tau, as well as other rare tauopathies. Moreover, neuronal accumulations of -synuclein in Lewy bodies and Lewy neurites are the pathological signatures of sporadic Parkinson disease (PD) and PD with dementia, as well as of dem

39、entia with Lewy bodies. Furthermore, almost all cases of amyotrophic lateral sclerosis (ALS) and a further subgroup of cases of FTLD (FTLD-TDP) are characterized by aggregates of TAR DNA-binding protein 43 (TDP43).Late-onset AD risk alleles by GWASHoltzman D, 2011TREM2How CJD is transmittedThe risk

40、of CJD is low. The disease cant be transmitted through coughing or sneezing, touching or sexual contact. The three ways it develops are:Sporadically. Most people with classic CJD develop the disease for no apparent reason. Termed spontaneous CJD or sporadic CJD, this type accounts for the majority of cases.By inheritance. In the United States, about 5 to 10 percent of people with CJD have a family history of the disease or test positive for a genetic mu