Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. No neuroprotective treatments have successfully prevented the progression of this disease. We report that p21-activated kinase 4 (PAK4) is a key survival factor for DA neurons. We observed PAK4 immunoreactivity in rat and human DA neurons in brain tissue, but not in microglia or astrocytes. PAK4 activity was markedly decreased in postmortem brain tissue from PD patients and in rodent models of PD. Expression of constitutively active PAK4S445N/S474E (caPAK4) protected DA neurons in both the 6-hydroxydopamine and a-synuclein rat models of PD and preserved motor function. This neuroprotective effect of caPAK4 was mediated by phosphorylation of CRTC1 [CREB (adenosine 3',5'-monophosphate response element-binding protein)-regulated transcription coactivator] at S215. The nonphosphorylated form of CRTC1S215A compromised the ability of caPAK4 to induce the expression of the CREB target proteins Bcl-2, BDNF, and PGC-1a. Our results support a neuroprotective role for the PAK4-CRTC1S215-CREB signaling pathway and suggest that this pathway may be a useful therapeutic target in PD.