The Threshold Theory for Parkinson's Disease

Trends Neurosci. 2017 Jan;40(1):4-14. doi: 10.1016/j.tins.2016.10.008. Epub 2016 Nov 25.


Parkinson's disease (PD) is recognized by the accumulation of α-synuclein within neurons. In contrast to the current ascending theory where α-synuclein would propagate from neuron to neuron, we now propose the threshold theory for PD based on evidence of parallel degeneration of both central nervous system (CNS) and peripheral nervous system (PNS) in PD. The functional threshold is lower for the emergence of early symptoms before the classical motor symptoms of PD. This is due to the larger functional reserve of the midbrain dopamine and integrated basal ganglia motor systems to control movement. This threshold theory better accounts for the current neurobiology of PD symptom progression compared to the hypothesis that the disease ascends from the PNS to the CNS as proposed by Braak's hypothesis.

Keywords: Parkinson's disease; dopaminergic neurons; functional threshold; spreading theory; α-synuclein.

Publication types

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

MeSH terms

  • Animals
  • Brain / physiopathology
  • Dopaminergic Neurons / physiology
  • Humans
  • Models, Neurological*
  • Parkinson Disease / physiopathology*