A Cortical Pathogenic Theory of Parkinson's Disease

Neuron. 2018 Sep 19;99(6):1116-1128. 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.

Keywords: Parkinson’s disease; alpha-synuclein; basal ganglia; cortex; corticostriatal; dopamine; nigrostriatal; somatotopy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain Mapping*
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiopathology
  • Dopaminergic Neurons / metabolism*
  • Humans
  • Parkinson Disease / pathology
  • Parkinson Disease / physiopathology*
  • Substantia Nigra / metabolism
  • Substantia Nigra / physiopathology*
  • alpha-Synuclein / metabolism


  • alpha-Synuclein