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

摘要

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 PIN death was obtained with organotypic slice cultures expressing the nr PIN phenotype, in which an inhibitor of tPA led to increased nr PIN survival. An antagonist of protein kinase C, a downstream component in the tPA pathway, also increased nr PIN 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 PIN mitochondrial morphology, dendritic growth, and synaptogenesis that culminate in nr PIN death and motor incoordination. We thus propose a molecular pathway by which the excessive tPA in nr cerebellum mediates PIN degeneration.