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Published on: June 23, 2023
Revisiting protein aggregation as pathogenic in sporadic Parkinson and Alzheimer diseases
Alberto J Espay1, Joaquin A Vizcarra2, Luca Marsili2
1From the UC Gardner Neuroscience Institute and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E., J.A.V., L.M., A.M.), Department of Neurology, University of Cincinnati, OH; Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic (A.E.L., A.F.), Toronto Western Hospital, University of Toronto; Krembil Research Institute (A.E.L., A.F.), Toronto, Canada; Parkinson's Disease and Movement Disorders Center (D.K.S.), Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; College of Medicine (K.A.J.), Mayo Clinic, Rochester, MN; Institute of Molecular and Clinical Sciences (F.M.), St George's University of London, UK; Division of Movement Disorders (R.S.), Department of Neurology and Department of Health Science Research, Mayo Clinic College of Medicine, Rochester, MN; Department of Neurology and the Pittsburgh Institute for Neurodegenerative Diseases (J.T.G., F.C.), University of Pittsburgh, PA; Department of Neurology (T.R.Y.), University of Kentucky, Lexington; Parkinson's Disease Research, Education and Clinical Center (C.M.T.), Neurology, San Francisco Veterans Affairs Medical Center; Department of Neurology (C.M.T.), University of California-San Francisco; Department of Neurology & Neurosurgery, Montreal Neurological Institute, and Department of Human Genetics (Z.G.-O.), McGill University, Canada; Parkinson & Other Movement Disorders Center UC San Diego (I.L.), Department of Neurosciences, Altman Clinical Translational Research Institute, La Jolla, CA; VA Puget Sound Health Care System and Department of Neurology (I.F.M., CP.Z.), University of Washington, Seattle; Department of Neurology (I.F.M.), University of Washington School of Medicine, Seattle; Center for Neurodegenerative Science (P.B.), Van Andel Research Institute, Grand Rapids, MI; Center for Neurological Restoration (H.H.F.) and Lou Ruvo Center for Brain Health, Neurological Institute (J.B.L.), Cleveland Clinic, OH; Department of Neurology (D.G.S.), University of Alabama at Birmingham; Consultorio y Laboratorio de Neurogenética (M.A.K.), Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA; Programa de Medicina de Precision y Genomica Clinica (M.A.K.), Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Buenos Aires, Argentina; Department of Neurology (M.A.S.), Massachusetts General Hospital, Boston; Division of Neuroscience (S.P.S.), Sanofi-Genzyme, Framingham, MA; Michael J. Fox Foundation for Parkinson's Research (T.S.), New York, NY; and College of Sciences (G.P.), University of Texas at San Antonio. alberto.espay@uc.edu.
Abstract:
The gold standard for a definitive diagnosis of Parkinson disease (PD) is the pathologic finding of aggregated α-synuclein into Lewy bodies and for Alzheimer disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinicopathologic-based nosology is the assumption that pathologic protein aggregation at autopsy reflects pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated α-synuclein in SNCA gene multiplication or aggregated β-amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These 3 conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinicopathologic criteria but instead on biological signals generated from large deeply phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.
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