12:00 AM
Sep 12, 2013
 |  BC Innovations  |  Targets & Mechanisms

All in the family

PTEN induced putative kinase 1 is a tantalizing player in familial forms of Parkinson's disease, in which it is inactivated by mutation, but thus far the kinase has been a no-fly zone for drug development because of challenges in activating kinases. Mitokinin LLC thinks it finally has an angle to modulate the kinase after the company's cofounders identified an ATP analog that selectively activates the target.1

The company plans to develop the analog or optimized variants to treat PD.

Mitochondria are particularly important for cells such as neurons that have a high demand for energy. Defects in mitochondrial quality control have been implicated in neurodegenerative conditions such as PD largely based on genetic mutations associated with familial, early onset forms of the disease.2,3

In particular, there have been multiple associations between disease and mutations that disrupt a process called mitophagy, or the ability of damaged mitochondria to self-destruct. Mitophagy is a cellular quality control mechanism that selectively eliminates the damaged organelle and thereby protects the cell from death.

Despite a solid genetic connection between disrupted mitophagy and PD, "we are only at the beginning of understanding the whole mitophagy pathway and, more generally, mitochondrial dysfunction associated with PD," said Helene Plun-Favreau, a senior lecturer in the Department of Molecular Neuroscience at the UCL Institute of Neurology.

To elucidate the molecular relationships between mitochondrial dysfunction and PD, a group led by Kevan Shokat focused on PTEN induced putative kinase 1 (PINK1). Shokat is a professor and chair of cellular and molecular pharmacology at the University of California, San Francisco.

PINK1 is a mitochondrial kinase that, in response to damage, accumulates in the outer mitochondrial membrane and recruits other proteins essential for mitophagy to the damaged organelle4 (see Box 1, "Targeting mitophagy in Parkinson's disease"). The gene is mutated in early onset, familial forms of PD.

To study PINK1, Shokat's group turned to its...

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