A Cortical Pathogenic Theory of Parkinson's Disease

Neuron
Guglielmo Foffani, José A Obeso

Abstract

In Parkinson's disease, the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) is associated with classic motor features, which typically have a focal onset. Since a defined somatotopic arrangement in the SNc has not been recognized, this focal motor onset is unexplained and hardly justified by current pathogenic theories of bottom-up disease progression (Braak's hypothesis, prionopathy). Here we propose that corticostriatal activity may represent a critical somatotopic "stressor" for nigrostriatal terminals, ultimately driving retrograde nigrostriatal degeneration and leading to focal motor onset and progression of Parkinson's disease. As a pathogenic mechanism, corticostriatal activity may promote secretion of striatal extracellular alpha-synuclein, favoring its pathological aggregation at vulnerable dopaminergic synapses. A similar pathogenic process may occur at corticofugal projections to the medulla oblongata and other vulnerable structures, thereby contributing to the bottom-up progression of Lewy pathology. This cortical pathogenesis may co-exist with bottom-up mechanisms, adding an integrative top-down perspective to the quest for the factors that impinge upo...Continue Reading

Citations

Mar 29, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Ronald B Postuma, Daniela Berg
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Aug 15, 2019·Movement Disorders : Official Journal of the Movement Disorder Society·Guglielmo FoffaniJosé A Obeso
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Nov 4, 2020·Brain : a Journal of Neurology·Claudia AmmannGuglielmo Foffani
Jan 21, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Mariana H G MonjeJosé A Obeso
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