Purkinje neuron degeneration in nervous (nr) mutant mice is mediated by a metabolic pathway involving excess tissue plasminogen activator

Proc Natl Acad Sci U S A. 2006 May 16;103(20):7847-52. doi: 10.1073/pnas.0602440103. Epub 2006 May 8.


Purkinje neurons (PNs), the central cells in cerebellar circuitry and function, constitute a vulnerable population in many human genetic, malignant, hypoxic, and toxic diseases. In the nervous (nr) mutant mouse, the majority of PNs die in the fourth to fifth postnatal weeks, but the responsible molecules are unknown. We first disclose a remarkable increase in mRNA expression and protein concentration in the nr cerebellum of tissue plasminogen activator (tPA), a gene closely linked to the mapped but as-yet-uncloned nr locus. Evidence that excessive tPA triggers nr PN death was obtained with organotypic slice cultures expressing the nr PN phenotype, in which an inhibitor of tPA led to increased nr PN survival. An antagonist of protein kinase C, a downstream component in the tPA pathway, also increased nr PN survival. Additional downstream targets in the tPA pathway (the mitochondrial voltage-dependent anion channel, brain-derived neurotrophic factor, and neurotrophin 3) were also abnormal, in parallel with the alterations in PN mitochondrial morphology, dendritic growth, and synaptogenesis that culminate in nr PN death and motor incoordination. We thus propose a molecular pathway by which the excessive tPA in nr cerebellum mediates PN degeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Cerebellum / cytology
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Chromosomes, Human, Pair 8
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Neurologic Mutants / anatomy & histology
  • Mice, Neurologic Mutants / physiology*
  • Mitochondria / metabolism
  • Phenotype
  • Purkinje Cells / cytology
  • Purkinje Cells / metabolism*
  • Purkinje Cells / pathology*
  • Testis / metabolism
  • Tissue Plasminogen Activator / metabolism*
  • Voltage-Dependent Anion Channels / genetics
  • Voltage-Dependent Anion Channels / metabolism


  • Voltage-Dependent Anion Channels
  • Tissue Plasminogen Activator