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...

The molecular mechanisms mediating degeneration of midbrain dopamine neurons in Parkinson's disease (PD) are poorly understood. Here, we provide evidence to support a role for the involvement of the calcium-dependent proteases, calpains, in the loss of dopamine neurons in a mouse model of PD. We show that administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase in calpain-mediated proteolysis in nigral dopamine neurons in vivo. Inhibition of calpain proteolysis using either a calpain inhibitor (MDL-28170) or adenovirus-mediated overexpression of the endogenous calpain inhibitor protein, calpastatin, significantly attenuated MPTP-induced loss of nigral dopamine neurons. Commensurate with this neuroprotection, MPTP-induced locomotor deficits were abolished, and markers of striatal postsynaptic activity were normalized in calpain inhibitor-treated mice. However, behavioral improvements in MPTP-treated, calpain inhibited mice did not correlate with restored levels of striatal dopamine. These results suggest that protection against nigral neuron degeneration in PD may be sufficient to facilitate normalized locomotor activity without necessitating striatal reinnervation. Immunohistochemical analyses of postmortem midbrain tissues from human PD cases also displayed evidence of increased calpain-related proteolytic activity that was not evident in age-matched control subjects. Taken together, our findings provide a potentially novel correlation between calpain proteolytic activity in an MPTP model of PD and the etiology of neuronal loss in PD in humans.

Highlights d Microglia engulf and eliminate synapses in the visual thalamus of MS patients d MS-relevant animal models show synapse engulfment and loss occur early in disease d Complement C3, but not C1q, localizes to synapses in demyelinating disease d AAV-Crry inhibits C3 and microglia-mediated synapse loss and preserves function