Enteric Neurodegeneration is Mediated Through Independent Neuritic and Somal Mechanisms in Rotenone and MPP+ Toxicity

Neurochem Res. 2018 Dec;43(12):2288-2303. doi: 10.1007/s11064-018-2649-x. Epub 2018 Sep 27.


Gut motility malfunction and pathological changes in the enteric nervous system (ENS) are observed in the early stages of Parkinson's disease (PD). In many cases disturbances in the autonomous functions such as gut motility precedes the observed loss of central motor functions in PD. However, the mechanism by which ENS degeneration occurs in PD is unknown. We show that parkinsonian mimetics rotenone and MPP+ induce neurite degeneration that precedes cell death in primary enteric neurons cultured in vitro. If the neuronal death signals originate from degenerating neurites, neuronal death should be prevented by inhibiting neurite degeneration. Our data demonstrate that overexpression of cytNmnat1, an axon protector, maintains healthy neurites in enteric neurons treated with either of the parkinsonian mimetics, but cannot protect the soma. We also demonstrate that neurite protection via cytNmnat1 is independent of mitochondrial dynamics or ATP levels. Overexpression of Bcl-xl, an anti-apoptotic factor, protects both the neuronal cell body and the neurites in both rotenone and MPP+ treated enteric neurons. Our data reveals that Bcl-xl and cytNmnat1 act through separate mechanisms to protect enteric neurites. Our findings suggest that neurite protection alone is not sufficient to inhibit enteric neuronal degeneration in rotenone or MPP+ toxicity, and enteric neurodegeneration in PD may be occurring through independent somatic and neuritic mechanisms. Thus, therapies targeting both axonal and somal protection can be important in finding interventions for enteric symptoms in PD.

Keywords: Enteric; Neurites; Neurons; Nmnat; Parkinson’s.

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity*
  • Animals
  • Cells, Cultured
  • Enteric Nervous System / drug effects*
  • Enteric Nervous System / pathology
  • Female
  • Insecticides / toxicity
  • MPTP Poisoning / chemically induced
  • MPTP Poisoning / pathology
  • Mice
  • Nerve Degeneration / chemically induced*
  • Nerve Degeneration / pathology
  • Neurites / drug effects*
  • Neurites / pathology
  • Parkinson Disease, Secondary / chemically induced*
  • Parkinson Disease, Secondary / pathology
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / pathology
  • Pregnancy
  • Rotenone / toxicity*


  • Insecticides
  • Rotenone
  • 1-Methyl-4-phenylpyridinium