Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1؊͞؊ mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1؊͞؊ embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1؊͞؊ mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults. P arkinson's disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity, akinesia, and postural instability (1). The cause of PD remains unknown, but epidemiological and genetic studies have suggested that the observed loss of dopaminergic neurons in PD is due to defects in common intracellular signaling pathways (2). Genes linked to familial PD include ␣-synuclein (3), Parkin (4), UCH-L1 (5), PINK1 (6), and dardarin (7). Proteins encoded by these genes are thought to be involved in protein aggregation and proteasome function, processes which, when disrupted in model systems, can also result in noninherited forms of PD (8). Recently, loss-of-function mutations in the DJ-1 locus were found in families with autosomal recessive early-onset PD (9). Additional studies have confirmed other DJ-1 mutations in various PD cohorts (10). DJ-1 was initially cloned as a putative oncogene (11) and as part of an RNA-binding complex (12). DJ-1 is highly expressed by normal astrocytes (13) and has been implicated in fertilization (14) and tumorigenesis (15,16). Studies of the crystal structure of DJ-1 (17) suggest that a particular DJ-1 mutation (L166P) reduces DJ-1 protein stability (18)(19)(20), resulting in degradation through the ubiquitin-proteasome system (21, 22). However, the physiological function of DJ-1 remains largely unknown.Motor impairments in PD patients result from inhibition of the nigrostriatal motor pathway. This inhibition is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) (8). The cause of the dopaminergic neuron loss remains unknown, but oxidative stress leading to apoptotic neuronal death has been implicated (23). Various neurotoxic paradigms have been studied in an effort to reproduce oxidative stress leading to neuronal loss in the SNc. Of these, administration of the well characterized meperidine analogue 1-methyl-4-phenyl-1,2,3,6-te...

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ͉ neurodegeneration P arkinson's disease (PD) is a neurodegenerative disorder characterized by disabling motor abnormalities, including tremor, muscle rigidity, paucity of voluntary movements, and postural instability (1). In several mammalian species, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces most of the biochemical and pathological alterations seen in PD, including the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) (1). Current treatment strategies for PD consist primarily of dopamine replacement therapy with levodopa or dopamine agonists (1). Although effective in the early stages of the disease, chronic dopamine replacement therapy can cause debilitating side effects. Accordingly, concerted research efforts have been focused on developing neuroprotective strategies that will halt or slow the progression of PD.Recent evidence implicates cyclin-dependent kinases (CDKs) in the pathogenesis of several neurodegenerative disorders. CDKs are serine͞threonine kinases best characterized for their role in cell cycle progression. To be active, CDKs require binding to specific regulatory partners such as cyclins (2). Up-regulation of a variety of cell cycle-related CDKs and͞or cyclins has been reported in a number of in vitro neuronal death paradigms (3-8).The importance of such observations is substantiated by reports that inappropriate activation of cell cycle-related pathways has been correlated with the pathogenesis of stroke (9, 10) and Alzheimer's disease (11). However, the identity and functional requirement of individual CDK members in neurodegeneration remain to be elucidated.In contrast to the mitotic CDKs, cdk5 activity is predominantly, although not exclusively, associated with postmitotic neurons (12). cdk5 activation requires association with its regulatory partner, p35 (13) or p39 (14). The p35͞cdk5 complex is required for proper development of the central nervous system (15, 16), process outgrowth (17), axonal migration (18, 19), cortical lamination (16, 20), cell adhesion (20), axonal transport (21), and synaptic activity (22). Just as with cell cycle-related CDK...