It has been over 20 years since JUN amino-terminal kinases (JNKs) were identified as protein kinases that are strongly activated by cellular stress and that have a key role in apoptosis. Examination of Jnk-knockout mice and characterization of JNK behaviour in neuronal cells has further revealed the importance of the JNK family in the nervous system. As well as regulating neuronal death, JNKs govern brain morphogenesis and axodendritic architecture during development, and regulate important neuron-specific functions such as synaptic plasticity and memory formation. This Review examines the evidence that the spatial segregation of JNKs in neurons underlies their distinct functions and that compartment-specific targeting of JNKs may offer promising new therapeutic avenues for the treatment of diseases of the nervous system, such as stroke and neurodegenerative disorders.

Selected vulnerability of neurons in Huntington’s disease (HD) suggests alterations in a cellular process particularly critical for neuronal function. Supporting this idea, pathogenic Htt (polyQ-Htt) inhibits fast axonal transport (FAT) in various cellular and animal HD models (mouse and squid), but the molecular basis of this effect remains unknown. Here we show that polyQ-Htt inhibits FAT through a mechanism involving activation of axonal JNK. Accordingly, increased activation of JNK was observed in vivo in cellular and animal HD models. Additional experiments indicate that polyQ-Htt effects on FAT are mediated by the neuron-specific JNK3, and not ubiquitously expressed JNK1, providing a molecular basis for neuron-specific pathology in HD. Mass spectrometry identified a residue in the kinesin-1 motor domain phosphorylated by JNK3, and this modification reduces kinesin-1 binding to microtubules. These data identify JNK3 as a critical mediator of polyQ-Htt toxicity and provides a molecular basis for polyQ-Htt-induced inhibition of FAT.