Death by phosphorylation

A tale of protein overproduction in Parkinson’s disease

In a recent issue of the journal Cell, a group of scientists from Johns Hopkins University School of Medicine identified a cause of brain-cell death leading to neurodegeneration in Parkinson’s disease. Their research findings not only are a significant achievement in Parkinson’s disease research but also may open avenues to explore new drug targets for the devastating disease.

Parkinson’s is a neurodegenerative disorder affecting about 1 percent of people older than 60. The cause is unknown, but a majority of patients show genetic predispositions. A number of genes have been found to be mutated; one such mutant gene, leucine-rich repeat kinase 2, or LRRK2, plays a significant role and appears in up to 40 percent of Parkinson’s cases in North African Arab and Ashkenazi Jewish populations. The mutation leads to the hyperactivity of LRRK2, but how elevated kinase activity contributes to neurodegeneration and disease progression was unknown until recently.

In their study, lead authors Ted and Valina Dawson and first author Ian Martin revealed the role of LRRK2 and identified its mysterious substrate contributing to Parkinson’s disease. They found that mutant LRRK2 phosphorylates ribosomal protein s15 at a higher rate than normal LRRK2, resulting in a significant increase in protein synthesis and leading to neurotoxicity.

“We have achieved a significant milestone in Parkinson’s disease research by identifying LRRK2 kinase substrate,” Ted Dawson says. The team is working on multiple hypotheses to understand “why bulk mRNA translation (protein synthesis) kills dopamine-(producing) neurons.”

One of the leading hypotheses his team testing is “if mutant LRRK2 kinase can change the gene-specific translational profile in dopamine-producing neurons that underlies mutant LRRK2 toxicity in Parkinson’s disease,” Dawson says.

He suggests mechanisms that might be responsible for the death of neuronal cells after hyper-phosphorylation: “Since translational output of a cell depends upon environmental conditions and cellular requirements, an aberrant increase in protein synthesis may make neurons energy deficient or result in extra stress on the protein folding/degradation pathway, leading to failure of protein quality control, or it may impair the ability of cells to respond to stress and lose tight translational control.”

Alok UpadhyayAlok Upadhyay (alok7930@gmail.com) is a postdoctoral associate at Fox Chase Cancer Center. His major research area is Notch signaling regulation during cell fate decisions and neural crest stem cell development. Follow him on Twitter at www.twitter.com/alok7667.