Cleaning the Slate: Erasing Toxic Brain Aggregates with the PINK1/Parkin ‘Magic Eraser’

Kumar Suresh, Ph.D,   Progenra Inc.

Cells in the human body employ two remarkable trash removal systems, the proteasome and the lysosome. Unlike your once-in-a week municipal trash removal set up, the cellular waste disposal system has to work round the clock to keep a clean and functional cellular environment. Of particular importance is the efficient removal of toxic aggregates which are known to cause death of neurons leading to neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).

 It has been known for a long time that certain proteins are more prone to forming toxic aggregates in the brain. For example, tau and Aβ proteins are known to accumulate as pathological aggregates in the AD brain whereas α-synuclein aggregates are found in the PD brain. Obviously, there is a defect in the brain’s trash removal system. The key question is,  can we fix this defect? and more importantly, can this fix halt the course of these devastating diseases?

  The answer is yes!  Scientists have recently uncovered a new mechanism by which cells can accelerate the clearance of toxic aggregates. Interestingly, this mechanism is intimately associated with mitochondria, the cellular energy factory and a key signaling hub. It turns out that the toxic protein aggregates stick to mitochondria causing serious damage as well as choking their ability to  produce ATP, the cellular energy currency.

The mitochondria located PTEN-induced putative kinase 1 (PINK1) acts as a mitochondria damage sensor.  Mutations in PINK1 and its functional partner Parkin E3 ligase can cause early onset PD. In healthy mitochondria the PINK1 levels are kept low due to its degradation by the proteasomes. Upon mitochondrial damage, PINK1 is stabilized and activated on mitochondria where it phosphorylates ubiquitin (phopsho-Serine65-Ub) which then recruits cytosolic Parkin to mitochondria. The Ser65 residue in Parkin also gets phosphorylated by PINK1 leading to the full activation of this otherwise inactive E3 ubiquitin ligase. Parkin then goes on to decorate mitochondria with phospho-ubiquitin containing polyubiquitin chains which are recognized by autophagic receptor proteins resulting in engulfment and degradation of damaged mitochondria in a process called mitophagy. Along with damaged mitochondria, the sticky proteins aggregates are also removed during mitophagy. Thus, cells have an ingenious way of getting rid of the toxic trash as long as the system can be kept functional.

PINK1 mutations that reduce the kinase activity or Parkin mutations that reduce the E3 ligase activity can lead to accumulation of damaged mitochondria and toxic protein aggregates which can be detrimental to the  neurons. In addition, as humans get older, the cellular trash removal system becomes less efficient. Most importantly, overexpression of PINK1 has been shown to promote removal of toxic tau and α-synuclein protein aggregates from the brain and improve brain function in animal models of AD and PD.

A recent study has shown that small molecule activators of PINK1 can promote mitophagy as well as the removal of toxic α-synuclein aggregates in animal brain. Progenra has developed highly potent PINK1 activators that promote mitophagy and removal of toxic tau aggregates.   Future studies will evaluate the effectiveness of PINK1 activators in treating AD and PD in human patients.

In PINK1 activators, we have a new drug tool to help the brain get rid of the trash and maintain a clean and functional cellular environment. We strongly believe that these new drugs will halt the process of neurodegeneration in AD and PD patients.