Breakthrough on the Horizon
My laboratory has been on the forefront of understanding the nuts and bolts of why neurons die in Parkinson’s disease (PD). One of our discoveries is on the verge of being rigorously tested in humans. It has the promise of becoming a breakthrough therapy for PD, in that it may potentially slow the progression of PD and stop the neurodegeneration that causes it. Neuropathologically, PD is characterized by the accumulation and aggregation of α-synuclein, which contributes to Lewy Body formation. There have been numerous studies linking α-synuclein to neurodegeneration. Several biological processes influence α-synuclein aggregation and toxicity. Our discovery involves a protein named c-Abl that phosphorylates and changes the function of other proteins.
c-Abl is a protein found within the genome of mammals and it has been shown to be involved in cell functions and stress responses. c-Abl phosphorylates two proteins that are critically involved in PD. Protein phosphorylation happens during the process of cells generating new functions for proteins. Phosphorylation of a protein typically results in the activation or inactivation of that protein’s function.
In September of 2010, our lab showed that c-Abl phosphorylates parkin on tyrosine 143. The parkin protein (generated by the parkin gene) is part of the ubiquitin-proteasome system that regulates the targeting of proteins for degradation. Mutations in parkin are the most common cause of autosomal recessive PD. The phosphorylation of parkin by c-Abl leads to its inactivation in sporadic PD and the accumulation of AIMP2 and PARIS. Parkin normally facilitates the removal of proteins such as AIMP2 and PARIS preventing them from harming the brain. We showed that deletion of the gene encoding c-Abl was protective in the MPTP intoxication model PD providing the first piece of evidence that inhibition of c-Abl could be neuroprotective in PD. Other investigators reported similar findings shortly after our publication.
In June 2016, my team released a study examining the relationship between c-Abl and α-synuclein. In mice expressing a human α-synucleinopathy–associated mutation, deletion of the gene encoding c-Abl reduced α-synuclein aggregation, neuropathology, and neurobehavioral deficits. It also significantly prolonged the life of the mice expressing the human α-synucleinopathy–associated mutation. The reverse was also true. Overexpression of overactive c-Abl in mice expressing the human α-synucleinopathy–associated mutation accelerated α-synuclein aggregation, neuropathology, neurobehavioral deficits and led to premature lethality. In this work, we showed that α-synuclein was phosphorylated by c-Abl on tyrosine 39 and that the phosphorylation of α-synuclein participated in the neuropathology. Others have also shown that α-synuclein is phosphorylated by c-Abl and inhibition of c-Abl protects against the neurodegeneration induced by α-synuclein. In addition, c-Abl inhibitors, in mice intoxicated with MPTP to induce Parkinsonian symptoms prevent the loss of dopamine neurons and the accompanying behavioral deficits. Together these studies established that c-Abl plays a critical role in α-synuclein induced degeneration and added to the evidence that inhibition of c-Abl may be neuroprotective in PD.
This double whammy (c-Abl phosphorylation of α-synuclein and parkin) seems to be a key lynch-pin in neurodegeneration in PD since inhibiting or lowering the levels of c-Abl in PD animal models prevents PD-like symptomatology. These studies make a strong case for testing other c-Abl inhibitors. It is also important to note that c-Abl inhibitors have been used safely to treat cancer patients for years. Building on this past success, there is a robust and active search for safe, brain penetrant drugs that inhibit the activity of c-Abl in PD.
If drugs that block the action of c-Abl work in humans like they do in animal models of PD, they will revolutionize the treatment of PD.
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Supporting Scientific Articles :
Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration.
Brahmachari S, Ge P, Lee SH, Kim D, Karuppagounder SS, Kumar M, Mao X, Shin JH, Lee Y, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM, Ko HS.
J Clin Invest. 2016 Aug 1;126(8):2970-88. doi: 10.1172/JCI85456. Epub 2016 Jun 27.
PMID: 27348587
Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS.
Sci Rep. 2014 May 2;4:4874. doi: 10.1038/srep04874.
PMID: 24786396
Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC, Dawson VL, Dawson TM.
Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16691-6. doi: 10.1073/pnas.1006083107. Epub 2010 Sep 7.
PMID: 20823226
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Ted Dawson was assisted by Kathleen Jordan in the writing of this blog.
Ted Dawson, MD, PhD was the WPC 2010 Program Chair and has been involved in many past Congresses as a committee member or speaker. He is the current Director of the Institute for Cell Engineering at John Hopkins University School of Medicine in Baltimore, Maryland.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.