Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults.
Deregulation of cyclin-dependent kinase 5 (Cdk5) is believed to play an important role in neurodegenerative diseases including PD. p25 is a cleavage peptide of p35, a physiologic activator of Cdk5. p25 combines to Cdk5 and leads to the hyperactivity of Cdk5, which in turn hyperphosphorylates downstream substrates and leads to neuroinflammation and apoptosis of neurons.
It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.
The levels of CSF NF-L detected in p25 mice are about 4-fold higher than the CSF levels detected in patients with chronic neurodegenerative diseases, such as symptomatic FTD (bvFTD).
Cyclin-dependent kinase 5 (CDK5) and cyclin-dependent kinase 5, regulatory subunit 1 (CDK5R1), encoding CDK5 activator p35, have a fundamental role in central nervous system (CNS) development and function, and are involved in the pathogenesis of several neurodegenerative disorders, thus constituting strong candidate genes for the onset of intellectual disability (ID).
Thus, a critical question is whether p23 and/or p19 could serve as an in vivo marker for neurodegenerative diseases featuring misfolded proteins and cellular stress.
The deregulation of cyclin-dependent kinase 5 (Cdk5) by p25 has been shown to contribute to the pathogenesis in a number of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD).
The activity of Cdk5 and its regulatory subunit p35 is thought to be important in both normal brain function and neurodegenerative disease pathogenesis.
It has been widely accepted that aberrant Cdk5 activity induced by the conversion of p35 to p25 plays roles in the pathogenesis of neurodegenerative diseases.
These results suggest that p35 transduction of neurons by viral vectors could be therapeutically useful in the treatment of human neurodegenerative diseases.