Peptides Derived from Neuronal Cell Cycle like Kinase 5 Activator p35, inNeurodegeneration; Pathology and Therapy

Abstract

Neurodegenerative disorders such as Alzheimer’s or Parkinson’s are diseases of aging. Mutations, lesions, neuronal insults, the genetic and stochastic “slings and arrows” of living, accumulate and downgrade organ function. Microarray analyses of aging brain identify patterns of genetic changes that correlate with neurodegenerative phenotypes. Genes involved in synaptic transmission, mitochondrial function and protein turnover are downregulated while significant numbers of genes regulating DNA repair, stress responses and inflammation are upregulated. This impact on the brain induces, a complex, multidimensional network of abnormal interactions leading to deposits of protein aggregates such as amyloid plaques, tau and neurofilament proteins tangles. For some, this pathology leads to neuron loss, behavioral defects, cognitive decline and death. Therapeutic approaches for AD, for example, target the molecular pathways leading to plaques and tangles; these include kinases and phosphatases. Among kinases, one stands out, Cdk5/p35, essential for neuronal migration, synapse formation, function and survival. Studies have shown that aging-induced neuronal stress deregulates and hyper activates Cdk5, a ubiquitous feature of neuronal disorders such as Alzheimer’s, Amyotropic lateral sclerosis (ALS) and Parkinson’s (PD). Among its many effects, hyperactive Cdk5 is implicated in the production of abnormal phosphorylated protein aggregates and is a therapeutic target. Roscovitine and related compounds inhibit Cdk5 activity but not specifically; cell cycle Cdks and other kinases are equally affected. In our laboratory two truncated peptides CIP (126a.a) and P5 (24a.a.), derived from p35, activator, of Cdk5 have been shown to specifically inhibit hyperactive Cdk5 in vitro, in cortical neurons and in AD, ALS and PD model mice. As a result the neurodegenerative phenotype was diminished; aggregates and inflammation were reduced, abnormal behavior was improved and increased animal’s longevity. We believe these peptides are excellent therapeutic candidates for those neurodegenerative disorders expressing hyperactive Cdk5 in the brain.