Trends in Neurosciences
OpinionInducible proteopathies
Introduction
In a remarkable variety of neurological and systemic disorders, specific proteins accumulate within cells and tissues, usually as a result of a change in protein conformation that renders the molecules prone to self-aggregation and resistant to clearance. These conformational diseases, or ‘proteopathies’, comprise systemic amyloidoses in addition to neurodegenerative conditions that are marked by the buildup of characteristic proteins in the brain, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and prion diseases 1, 2, 3, 4. In this article, we consider the mechanistic commonalities among seemingly distinct protein-based diseases, and in particular emerging evidence that some proteopathies can be induced in animal models by exposure to exogenous material. We argue that an understanding of the earliest events that induce protein misconformation and aggregation in vivo will yield more focused strategies for discovering treatments for these devastating diseases.
Section snippets
Induction of prion diseases
Prion diseases, although rare, have attracted special attention because of their lethality and unorthodox transmissibility. They include Creutzfeldt–Jakob disease, kuru, fatal familial insomnia and Gerstmann–Sträussler–Scheinker syndrome in humans, and several diseases in nonhuman species, the best known being scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, transmissible mink encephalopathy, and chronic wasting disease in deer and elk [5]. Prion diseases are typified
Applying the prion model of induction to other proteopathies
In the mid-1800s, Rudolf Virchow first employed the term ‘amyloid’, meaning ‘starch-like’, to describe accumulations of an unusual substance in animal organs that stained in a similar way to some constituents of plants. Today, ‘amyloid’ is generally used to describe fibrillar aggregates of particular proteins that have assumed a non-native, β-sheet-rich configuration. More than 20 proteins are known to form disease-related amyloid deposits in vivo, each having a unique amino acid sequence and
Induction of amyloid A amyloidosis
Under chronic inflammatory conditions that increase the hepatic production of amyloid A protein, the levels of amyloid A rise dramatically in blood, and this protein accumulates as amyloid fibrils in systemic organs, including the kidneys, liver and spleen [23]. With time, the burgeoning amyloid load triggers the impairment or failure of organ function. In animal models, administration of a systemic inflammatory stimulus (such as silver nitrate) eventually causes amyloid A deposition, but the
Induction of apolipoprotein AII amyloidosis
Apolipoprotein AII (ApoAII) is an abundant, yet poorly understood, apolipoprotein [27] that can deposit spontaneously as amyloid fibrils in aged mice [28] and in a hereditary human disease caused by a stop-codon mutation in the APOA2 gene [29]. Mouse senile amyloidosis entails the accumulation of ApoAII in systemic organs, a process that can be stimulated by peripheral injection of ApoAII fibrils isolated from affected liver [28]. ApoAII also induces amyloid disease when introduced into the
Induction of Aβ proteopathy
Aβ is a minor proteolytic cleavage product of the Aβ-precursor protein (βAPP), a ubiquitous, type-1 transmembrane protein that is abundant in brain. Aβ, like other proteopathic molecules, is liable to misconformation and aggregation into macromolecular assemblies such as oligomers and amyloid fibrils. Aggregated Aβ constitutes the cores of senile plaques, and forms deposits in the walls of brain blood vessels known as cerebral Aβ angiopathy. In humans and several other mammalian species, the
Inducible proteopathies: some caveats
The transmission of prion diseases is relatively unambiguous because the clinical manifestations (ultimately death) are particularly obvious 2, 5. By contrast, the neurological consequences of cerebral Aβ amyloidosis, especially in non-human species, often are more subtle and variable than those of the prionoses 22, 38, 39, 42. As a result, the effects of ‘infection’ might be relatively difficult to discern in some proteopathies, at least from a functional standpoint. This matter is complicated
Concluding remarks
The weight of evidence now supports the concept that exogenous, structurally complementary molecules can induce specific diseases of protein conformation and assembly in animals. Key objectives for future research are to define, at the molecular level, how disease originates de novo in both the sporadic and the hereditary proteopathies, to establish the structural idiosyncrasies of agents that act as corruptive protein templates, and to elucidate the cytotoxic mechanisms of protein aggregates.
Acknowledgements
We gratefully acknowledge helpful discussions with John Hardy, Ingo Autenrieth, Rolf Warzok, Margaret Walker and Rebecca Rosen. This work was supported by grants from the Woodruff Foundation, NIH RR-00165, by the Sanders-Brown Center on Aging and Chandler Medical Center of the University of Kentucky, by the National Institute on Aging Intramural Research Program of the NIH, and by the Alzheimer's Association.
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