MPTP activates c-Jun NH2-terminal kinase (JNK) and its upstream regulatorykinase MKK4 in nigrostriatal neurons in vivo

The neuropathology of Parkinson's disease is reflected in experimental anim als treated with the selective nigrostriatal dopaminergic neurotoxin MPTP. Neurons exposed to MPTP (MPP+) express morphological features of apoptosis, although the intracellular pathways that produce this morphology have not been established. The c-Jun NH2-terminal kinase (JNK) signaling cascade has been implicated as a mediator of MPTP-induced apoptotic neuronal death bas ed on the ability of CEP-1347/KT-7515, an inhibitor of JNK activation, to a ttenuate MPTP-induced nigrostriatal dopaminergic degeneration. In these stu dies, MPTP-mediated activation of the JNK signaling pathway was assessed in the nigrostriatal system of MPTP-treated mice. MPTP elevated levels of pho sphorylated JNK and JNK kinase (MKK4; also known as SEK1 or JNKK), by 2.5- and fivefold, respectively. Peak elevations occurred soon after administrat ion of MPTP and coincided with peak CNS levels of MPP+. Increased MKK4 phos phorylation, but not JNK phosphorylation, was found in the striatum, sugges ting that activation of MKK4 occurs in injured dopaminergic terminals. Both JNK and MKK4 phosphorylations were attenuated by pretreatment with l-depre nyl, indicating that these phosphorylation events were mediated by MPP+. Mo reover, CEP-1347/KT-7515 inhibited MPTP-mediated MKK4 and JNK signaling at a dose that attenuates MPTP-induced dopaminergic loss. These data implicate this signaling pathway in MPTP-mediated nigrostriatal dopaminergic death a nd suggest that it may be activated in the degenerative process in Parkinso n's disease.