Programmed cell death (PCD) of neurons has long been considered to be essential for development and function of nervous system. However, Bax-deleted animals with a complete prevention of PCD can form normal neural circuitry and exhibit normal behavior. This surprisingly normal phenotype is due to the compensatory atrophy, i.e. retraction of the neuronal processes and shrinkage of cell bodies of the surplus neurons. Atrophic changes of neurons were also observed following the blockade of PCD in animal models of neurodegenerative diseases. For example, dopaminergic neurons in Bax-deleted mice were resistant to the 6-hydroxydopamine (6-OHDA)-induced neuronal insults, and PCD was completely blocked. However, those survived DA neurons were markedly atrophied, without any improvements in Parkinson disease (PD)-like functions. On the other hand, genetic deletion of Poly [ADP-ribose] polymerase 1 (PARP-1) completely blocked both 6-OHDA-induced dopaminergic neurodegeneration and related PD-like symptoms. We found that hyper-activation of PARP-1 depleted ATP pools in the DA neurons, thereby activating AMP-activated protein kinase (AMPK). Blockade of AMPK activation by viral infection of dominant negative AMPK (DN-AMPK) partially inhibited the DA neuronal degeneration. Collectively, these results suggest that manipulation of PARP1-AMPK pathway provides an effective therapeutic approach to prevent the atrophic modification of neurons associated with neurodegenerative progress and functional impairments.
- Programmed cell death
- Adult neurogenesis
- Mitochondrial dynamics
Awards and Honors:
- 2007 Best Article Award, Korean Federation of Science and Technology Societies (KOFST)
- 2012 Chair of Program Comittee for Asia-Pacific Society of Neurochemistry (APSN)