抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Peptides or proteins convert under some conditions from their soluble forms into highly ordered fibrillar aggregates. Such transitions can give rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we identify the diseases known to be associated with formation of fibrillar aggregates and the specific peptides and proteins involved in each case. We describe, in addition, that living organisms can take advantage of the inherent ability of proteins to form such structures to generate novel and diverse biological functions. We review recent advances toward the elucidation of the structures of amyloid fibrils and the mechanisms of their formation at a molecular level. Finally, we discuss the relative importance of the common main-chain and side-chain interactions in determining the propensities of proteins to aggregate and describe some of the evidence that the oligomeric fibril precursors are the primary origins of pathological behavior.

/pdf/protein-misfolding-functional-amyloid-and-human-disease-2w386pwb7k.pdf

Protein Misfolding, Functional Amyloid, and Human Disease

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Parkinson's disease: Mechanisms and models

The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.

Ordered protein aggregation in the brain is a hallmark of Alzheimer's disease and scrapie. The disease-specific amyloid fibrils comprise primarily a single protein, amyloid beta, in Alzheimer's disease, and the prion protein in scrapie. These proteins can be induced to form aggregates in vitro that are indistinguishable from brain-derived fibrils. Consequently, much effort has been invested in the development of in vitro model systems to study the details of the aggregation processes and the effects of endogenous molecules that have been implicated in disease. Selected studies of this type are reviewed herein. A simple mechanistic model has emerged for both processes that involves a nucleation-dependent polymerization. This mechanism dictates that aggregation is dependent on protein concentration and time. Furthermore, amyloid formation can be seeded by a preformed fibril. The physiological consequences of this mechanism are discussed.

MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins

Accelerated in vitro fibril formation by a mutant α-synuclein
linked to early-onset Parkinson disease

/pdf/accelerated-in-vitro-fibril-formation-by-a-mutant-alpha-2eeejew2vb.pdf

Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.

Two missense mutations in the gene encoding α-synuclein have been linked to rare, early-onset forms of Parkinson's disease (PD). These forms of PD, as well as the common idiopathic form, are characterized by the presence of cytoplasmic neuronal deposits, called Lewy bodies, in the affected region of the brain. Lewy bodies contain α-synuclein in a form that resembles fibrillar Aβ derived from Alzheimer's disease (AD) amyloid plaques. One of the mutant forms of α-synuclein (A53T) fibrillizes more rapidly in vitro than does the wild-type protein, suggesting that a correlation may exist between the rate of in vitro fibrillization and/or oligomerization and the progression of PD, analogous to the relationship between Aβ fibrillization in vitro and familial AD. In this paper, fibrils generated in vitro from α-synuclein, wild-type and both mutant forms, are shown to possess very similar features that are characteristic of amyloid fibrils, including a wound and predominantly unbranched morphology (demonstrated by...

Fibrils Formed in Vitro from α-Synuclein and Two Mutant Forms Linked to Parkinson's Disease are Typical Amyloid†

http://cml.harvard.edu/assets/ChemBiol_1997_4_119-125_Harper.pdf

Observation of metastable Aβ amyloid protofibrils by atomic force microscopy

Amyloid fibrils comprising primarily the peptides Aβ40 and Aβ42 are a defining feature of the Alzheimer's disease (AD) brain, and convergent evidence suggests that the process of their formation plays a central role in the AD pathogenic pathway. Elucidation of fibril assembly is critical for the discovery of potential AD diagnostics and therapeutics, since the pathogenic entity is not necessarily the product fibril, but could be a precursor species whose formation is linked to fibrillogenesis in vivo. Atomic force microscopy allowed the identification of an unanticipated intermediate in in vitro fibril formation, the Aβ amyloid protofibril. This manuscript describes studies of the structure of the Aβ40 protofibril and its in vitro assembly and disassembly using atomic force microscopy (AFM). The Aβ40 protofibril has a height of ca. 4.3 ± 0.5 nm and a periodicity of ca. 20 ± 4.7 nm. The rate of its elongation depends on the total concentration of Aβ40, the temperature, and ionic strength of the medium. Aβ4...

https://cml.harvard.edu/assets/biochemistry38_8972.pdf

James Harper

Papers

MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins

Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease.

Fibrils Formed in Vitro from α-Synuclein and Two Mutant Forms Linked to Parkinson's Disease are Typical Amyloid†

Observation of metastable Aβ amyloid protofibrils by atomic force microscopy

Assembly of A beta amyloid protofibrils: an in vitro model for a possible early event in Alzheimer's disease.