(精品) 神经退行性疾病的分子病理学研究进展课件

Protein deposition in the brain of different types of neurodegenerative diseases
Cerebral aggregates in neurodegenerative
diseases
Extracellular amyloid plaques (white arrows) and intracytoplasmic neurofibrillary tangles (yellow arrows) are the pathological signature of Alzheimer’s disease. Intracytoplasmic aggregates are typically present in the neurons of people affected by Parkinson’s disease and amyotrophic lateral sclerosis. Intranuclear inclusions of huntingtin are observed in Huntington’s disease patients and extracellular prion amyloid plaques that are located in 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).
Ubiquitin-Proteasome Proteolysis
Ubiquitin 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-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 activated 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 polyubiquitin 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.
Soluble misfolded monomers and dimers can be recognized by both the UPS or CMA(chaperone-mediated autophagy)-related chaperones, and subsequently degraded by either of these two pathways. In the case of CMA, cytosolic proteins (i.e., asynuclein) 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 protein, macroautophagy is the only mechanism available to clear the more insoluble and highly ordered aggregates.
AβDP: Aβ-degrading protease UPS Autophagy
Cold Spring Harb Perspect Med 2012, 2(6):a006379
基因突变或过表达可导致相关蛋白生成增加
Amyloid Precursor Protein (APP) and Its Processing
Huntingtin protein
舞蹈症
• Parkinson’s disease:
alpha-synuclein
➢ Lewy bodies form in brain cells
➢ Kill cells in part of brain (midbrain) that produces dopamine
Autophagy
Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the lysosomal machinery
神经退行性疾病分子病理学 研究进展
课程提纲
• 神经退行性疾病的病理变化 • 神经退行性疾病的致病因素及其机制 • 神经退行性疾病的研究进展
神经退行性疾病
神经退行性疾病（neurodegenerative diseases） 是一类慢性、随着年龄增长而进行性加重的神经 系统疾病，由神经退行性病变而引起。
➢ Less dopamine means motor control loss
The Lewy body is the pathological hallmark of Parkinson disease. Classical Lewy bodies are Lewy Body 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 halo (arrow). The protein alpha-synuclein is a component of the Alpha-synuclein Lewy body.
Nat Rev Neurosci 2003, 4:49-60
神经退行性疾病：蛋白质异常聚集
Nat Rev Neurosci 2003, 4:49-60
Abnormal Accumulation of Proteins in the Brain Is Dependent on Their ProBaidu Nhomakorabeauction and Clearance
causes self association of the protein in nerve cells ➢ intranuclear inclusions killing nerve cells
Polyglutamine (PolyQ) Repeat
>36 repeats in HD
• Huntington’s disease:
• Huntington’s disease:
Huntingtin protein
➢ inherited autosomal dominant disorder ➢ motor impairment, personality changes ➢ polyglutamine repeat in the Huntingtin protein of some people
Selkoe et al, 2001
基因突变或过表达可导致相关蛋白生成增加
Amyloid Precursor Protein (APP) and Its Processing
Selkoe et al, 2001
蛋白质错误折叠与异常聚集
Nat Rev Neurosci 2003, 4:49-60
蛋白质折叠异常影响蛋白质的降解和清除
The other conformational state (misfolded, disease-associated PrPSc (Sc meaning scrapieassociated) is very poorly water-soluble and readily forms protein aggregates.
Neurodegeneration is the term for the progressive loss of
structure or function of neurons, including death of neurons.
常见神经退行性疾病
Nat Rev Neurosci 2003, 4:49-60
Superoxide dismutase 1 (SOD1)
Nature Reviews Neuroscience 2013，14, 248-264
Prion protein
The native state (endogenous cellular prion protein, PrPC ) is water-soluble, presenting in healthy cells, with possible function in transmembrane transport or signaling;
Neuronal loss in Parkinson’s disease
中脑切片
ALS: amyotrophic lateral sclerosis
Superoxide dismutase(SOD1)/TDP-43/C9ORF72
Amytrophic lateral sclerosis. ALS is a progressive fatal disease caused by degeneration of lower motor neurons in the lateral horn of the spinal cord and upper motor neurons of the cerebral cortex, resulting in progressive motor weakness.