“Fatal Attractions” of Proteins: A Comprehensive Hypothetical Mechanism Underlying Alzheimer's Disease and Other Neurodegenerative Disorders

Authors

  • JOHN Q. TROJANOWSKI,

    Corresponding author
    1. The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA
      Address for correspondence: J.Q. Trojanowski, M.D., Ph.D., or V. M.-Y. Lee, Ph.D., Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney Building, 3rd floor, Philadelphia, Pennsylvania 19104-4283. Voice: 215-662-6399 or -6427; fax: 215-349-5909. trojanow@mail.med.upenn.edu [or] leevmy@mail.med.upenn.edu
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  • VIRGINIA M.-Y. LEE

    1. The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA
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Address for correspondence: J.Q. Trojanowski, M.D., Ph.D., or V. M.-Y. Lee, Ph.D., Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP, Maloney Building, 3rd floor, Philadelphia, Pennsylvania 19104-4283. Voice: 215-662-6399 or -6427; fax: 215-349-5909. trojanow@mail.med.upenn.edu [or] leevmy@mail.med.upenn.edu

Abstract

Abstract: Abnormal protein-protein interactions that result in the formation of intracellular and extracellular aggregates of proteinacious fibrils are common neuropathological features of many, albeit diverse, neurodegenerative disorders, such as sporadic and familial Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion encephalopathies. Indeed, increasing evidence suggests that abnormal protein-protein interactions and/or the lesions that result from the aggregation of pathological protein fibrils could play a mechanistic role in the dysfunction and death of neurons or glial cells in neurodegenerative diseases. Here we propose that “fatal attractions” between brain proteins are the key pathological events underlying Alzheimer's disease and a large number of other seemingly diverse neurodegenerative disorders. This hypothesis predicts that the abnormal interaction between normal brain proteins alters their conformation and promotes the assembly of these pathological conformers into filaments that progressively accumulate as intracellular or extracellular fibrous deposits in the central nervous system. Further, the transformation of the normal proteins into pathological conformers is predicted to result in losses of critical functions, and the disease proteins or their progressive accumulation into filamentous aggregates are predicted to acquire neurotoxic properties, all of which culminate in the dysfunction and death of affected brain cells. Thus, the “fatal attractions” hypothesis describes a plausible unifying mechanism that accounts for the onset/progression of Alzheimer's disease and a large number of other seemingly unrelated neurodegenerative disorders characterized neuropathologically by filamentous brain lesions formed by different proteins.

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