Trends in Neurosciences
Volume 29, Issue 8, August 2006, Pages 438-443
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Opinion
Inducible proteopathies

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Numerous degenerative diseases are characterized by the aberrant polymerization and accumulation of specific proteins. These proteopathies include neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and the prion diseases, in addition to diverse systemic disorders, particularly the amyloidoses. The prion diseases have been shown to be transmissible by an alternative conformation of the normal cellular prion protein. Other proteopathies have been thought to be non-transmissible, but there is growing evidence that some systemic and cerebral amyloidoses can be induced by exposure of susceptible hosts to cognate molecular templates. As we review here, the mechanistic similarities among these diseases provide unprecedented opportunities for elucidating the induction of protein misfolding and assembly in vivo, and for developing an integrated therapeutic approach to degenerative 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.

References (86)

  • M.J. Callahan

    Augmented senile plaque load in aged female β-amyloid precursor protein-transgenic mice

    Am. J. Pathol.

    (2001)
  • A. Piccini

    β-Amyloid is different in normal aging and in Alzheimer disease

    J. Biol. Chem.

    (2005)
  • B. O’Nuallain

    Seeding specificity in amyloid growth induced by heterologous fibrils

    J. Biol. Chem.

    (2004)
  • D. Hamada

    Engineering amyloidogenicity towards the development of nanofibrillar materials

    Trends Biotechnol.

    (2004)
  • D.M. Walsh et al.

    Deciphering the molecular basis of memory failure in Alzheimer's disease

    Neuron

    (2004)
  • N. Naslavsky

    Sphingolipid depletion increases formation of the scrapie prion protein in neuroblastoma cells infected with prions

    J. Biol. Chem.

    (1999)
  • M.P. Mattson et al.

    Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium

    Brain Res.

    (1995)
  • M.P. Mattson

    Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity

    Trends Neurosci.

    (1998)
  • A. Demuro

    Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers

    J. Biol. Chem.

    (2005)
  • R. Kayed

    Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases

    J. Biol. Chem.

    (2004)
  • B.J. Tabner

    Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia

    J. Biol. Chem.

    (2005)
  • G. Barja

    Free radicals and aging

    Trends Neurosci.

    (2004)
  • R.S. Balaban

    Mitochondria, oxidants, and aging

    Cell

    (2005)
  • T. Grune

    Decreased proteolysis caused by protein aggregates, inclusion bodies, plaques, lipofuscin, ceroid, and ‘aggresomes’ during oxidative stress, aging, and disease

    Int. J. Biochem. Cell Biol.

    (2004)
  • N. Chondrogianni et al.

    Proteasome dysfunction in mammalian aging: steps and factors involved

    Exp. Gerontol.

    (2005)
  • J.N. Keller

    Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain

    Int. J. Biochem. Cell Biol.

    (2004)
  • J.E. Kim et al.

    Fullerene inhibits β-amyloid peptide aggregation

    Biochem. Biophys. Res. Commun.

    (2003)
  • L.C. Walker et al.

    The cerebral proteopathies: neurodegenerative disorders of protein conformation and assembly

    Mol. Neurobiol.

    (2000)
  • S.B. Prusiner

    Shattuck lecture – neurodegenerative diseases and prions

    N. Engl. J. Med.

    (2001)
  • R.W. Carrell et al.

    Alpha1-antitrypsin deficiency – a model for conformational diseases

    N. Engl. J. Med.

    (2002)
  • J. Hardy et al.

    The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

    Science

    (2002)
  • E. McKintosh

    Prion diseases

    J. Neurovirol.

    (2003)
  • S.B. Prusiner

    The Prion Diseases

  • C. Weissman

    The state of the prion

    Nat. Rev. Microbiol.

    (2004)
  • J. Hardy

    Expression of normal sequence pathogenic proteins for neurodegeneration contributes to disease risk: ‘permissive templating’ as a general disease mechanism of neurodegeneration

    Biochem. Soc. Trans.

    (2005)
  • A. Aguzzi

    Immune system and peripheral nerves in propagation of prions to CNS

    Br. Med. Bull.

    (2003)
  • G. Legname

    Synthetic mammalian prions

    Science

    (2004)
  • B. Chesebro

    Anchorless prion protein results in infectious amyloid disease without clinical scrapie

    Science

    (2005)
  • Walker, L. et al. Koch's postulates and infectious proteins. Acta Neuropathol. (Berl.) (in...
  • P. Westermark

    Aspects on human amyloid forms and their fibril polypeptides

    FEBS J.

    (2005)
  • C.M. Dobson

    Protein folding and misfolding

    Nature

    (2003)
  • L.C. Walker et al.

    Proteopathy: the next therapeutic frontier?

    Curr. Opin. Investig. Drugs

    (2002)
  • D.C. Gajdusek

    Spontaneous generation of infectious nucleating amyloids in the transmissible and nontransmissible cerebral amyloidoses

    Mol. Neurobiol.

    (1994)
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