A Cortical Pathogenic Theory of Parkinson’s Disease

• Published in: Neuron (Cambridge, Mass.) Mass.), 2018-09, Vol.99 (6), p.1116-1128
• Main Authors: Foffani, Guglielmo, Obeso, José A.
• Format: Article
• Language: English
• Subjects: alpha-synuclein; alpha-Synuclein - metabolism; Animals; basal ganglia; Brain Mapping; Corpus Striatum - metabolism; Corpus Striatum - physiopathology; Cortex; corticostriatal; Dopamine; Dopamine receptors; Dopaminergic Neurons - metabolism; Humans; Medulla oblongata; Neostriatum; Nervous system; Neurodegeneration; nigrostriatal; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson's disease; Pathogenesis; Pathology; Propagation; Secretion; somatotopy; Substantia nigra; Substantia Nigra - metabolism; Substantia Nigra - physiopathology; Synapses; Synuclein
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2018.07.028

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 upon the vulnerability of dopaminergic cells in the onset and progression of Parkinson’s disease. Current pathogenic theories of Parkinson’s disease postulate a bottom-up progression, from the periphery to the neocortex. Foffani and Obeso offer a top-down perspective, proposing that corticostriatal activity may act as a somatotopic “stressor” for nigrostriatal neurons.