Cyclin-Dependent Kinase 5 – An Emerging Player in Parkinson’s Disease Pathophysiology

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder that affects 1% of the general population at age 65, with the prevalence rising to 4-5% by age 85 (de Rijk et al. 1997). Symptoms of PD include muscle rigidity, resting tremor, bradykinesia, postural instability, speech impediment and cognitive decline. At the cellular level, PD is characterized by selective degeneration of dopaminergic neurons in the substantia nigra, and the presence of cytoplasmic inclusions known as Lewy bodies in the brains of PD patients (Levy et al. 2009). Despite the prevalence of PD, therapeutic agents that slow or halt disease progression are lacking. Current treatments for PD are highly limited and focus predominantly on symptomatic relief. For example, the most effective treatment for ameliorating PD symptoms is administration of levodopa, a precursor that is converted to dopamine in the brain, to restore dopamine levels in PD patients. Nonetheless, the efficacy of levodopa wears off with prolonged treatment, in addition to triggering dyskinesia as a side effect (Obeso et al. 2010, Poewe et al. 2010). There is thus an urgent need to elucidate the cellular mechanism underlying PD pathology for the development of more effective treatments. The etiopathology of PD has remained largely enigmatic. Majority of the PD cases are idiopathic, although familial cases of PD with identifiable mutations also account for about 5% of all PD cases (Dauer and Przedborski 2003). Prior to the identification of these missense mutations, nonetheless, scientists have predominantly focused on the two known cellular hallmarks of PD, namely the degeneration of dopaminergic neurons and the presence of Lewy bodies. Since majority of the motor deficits exhibited by PD patients is reversed by elevating dopamine levels in the brain, it is believed that the motor symptoms of PD are due mostly to the loss of dopaminergic neurons in the substantia nigra (Obeso et al. 2010). This has sparked extensive research aimed at elucidating the mechanisms implicated in the degeneration of these neurons. Abnormality in various cellular processes have been linked to neuronal loss in PD, such as oxidative stress, mitochondrial dysfunction, aberrant proteasomal degradation and deregulation of the autophagy pathway (Levy et al. 2009). On the other hand, the precise role of Lewy bodies has become a little controversial. While protein aggregates and the presence of cytoplasmic inclusions have long been considered as toxic, recent evidence suggests that the aggregates may also exhibit neuroprotective roles by serving as traps for the toxic oligomeric forms (Rubinsztein 2006).