How does the most common genetic cause of Parkinson’s Disease (LRRK2) cause Parkinson’s disease and could it help us develop a better therapy?

You can find out more about NPF's National Medical Director, Dr. Michael S. Okun, by also visiting the NPF Center of Excellence, University of Florida Center for Movement Disorders & Neurorestoration. Dr. Okun is also the author of the Amazon #1 Parkinson's Best Seller 10 Secrets to a Happier Life.

Currently, approximately 10% of Parkinson’s disease cases have been associated with gene defects.  These changes in the DNA have allowed researchers to hone in on the mechanisms that may be responsible for this devastating disease. Scientists around the world have become adept at preparing animal models of Parkinson’s disease by using the observed changes in the DNA occurring in some human cases. Ted and Valina Dawson, a husband and wife team located at the National Parkinson Foundation Center of Excellence at Johns Hopkins in Baltimore, MD recently published an important paper on how the most common genetic subtype of Parkinson’s disease (LRRK2) leads to degeneration and to cell death. In this month’s What’s Hot in PD? Column I will discuss the findings from this exciting paper, and also cover the possible implications for the field.

Mutations in the DNA of Parkinson’s disease patients located in the leucine-rich repeat kinase 2 region (LRRK2) represent the most common genetic cause of Parkinson's disease. Because LRRK2 is the most common gene defect responsible for Parkinson’s disease, it has been a focus of many laboratories. So what does LRRK2 do? One of the jobs of LRRK2 in the brain seems to be to tag proteins. When proteins are tagged, this signals the brain to change its cell manufacturing process. However, when bad LRRK2 tags proteins, it results in over-manufacturing. An excess of proteins can lead to the death of brain cells. Bad LRRK2 performs its tagging function by attaching what have been referred to as phosphate groups. Bad LRRK2 leads to increases in proteins through its action on a part of the cell called ribosomal s15. The Dawsons demonstrated that removing the phosphate group tagging of s15 prevented degeneration. Further, by administering a low dose of anisomycin, which blocks protein production, the Dawson strategy also rescued flies with LRRK2 mutations.

Though these findings are exciting, we should remember that they have yet to be translated into humans. The Dawsons suggest that one way to treat LRRK2 Parkinson’s disease would be to simply block phosphorylation of the s15 ribosomal protein. This idea may be formulated into a strategy for a future human clinical drug trial. Further, if there is a clinical trial, we will need a way to measure success and to monitor s15 phosphorylation. Phosphorylation could possibly be a blood or other biomarker of bad LRRK2 activity. Though there are many steps remaining in human translation, the findings from this recent paper provide something for the Parkinson’s community to cheer about.

References:
Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL. Ribosomal Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson's Disease. Cell. 2014 Apr 10;157(2):472-85. doi:10.1016/j.cell.2014.01.064. PubMed PMID: 24725412.

Posted: 5/1/2014 6:00:00 AM by Cathy Whitlock


Browse current and archived What's Hot in PD? articles, the National Parkinson Foundation's monthly blog for people with Parkinson's written by our National Medical Director, Dr. Michael S. Okun. 

September 2014
Deep Brain Stimulation for Parkinson’s Disease: NPF Congratulates Mahlon DeLong and Alim-Louis Benabid and Looks to a Bright Future in Human Neural-Network Modulation

August 2014
Everything You Need to Know About Medical Marijuana and Parkinson’s Disease

July 2014
The End for Levodopa Phobia: New Study Shows Sinemet is a Safe Initial Therapy for Treatment of Parkinson's Disease

June 2014
Is light therapy a potential treatment modality in Parkinson’s disease?

May 2014
How does the most common genetic cause of Parkinson’s Disease (LRRK2) cause Parkinson’s disease and could it be used to help develop a better therapy?

April 2014
An Update on DAT Scanning for Parkinson’s Disease Diagnosis

March 2014
Could Northera (Droxidopa) Be an Alternative Treatment for Low Blood Pressure and Passing Out Symptoms?

February 2014
The Dream of a Pill Free Existence and the Continuous Dopaminergic Pump for the Treatment of Parkinson's Disease

January 2014
Should I take Inosine to Raise my Uric Acid Levels and Treat my Parkinson’s Disease?

December 2013
Could Fungus and Mold be an Important Contributor to Parkinson’s Disease?

November 2013
Pimavanserin and the Hope for a Better Drug for Hallucinations and Psychosis in Parkinson’s Disease

October 2013
Halting of the Creatine Study

September 2013
The Importance of Identifying and Treating Caregiver Strain

August 2013
Putting Parkinson’s Disease Information into the Palm of Your Hand: Parkinson’s Enters the Smartphon

July 2013
What Parkinson’s Disease Patients Need to Know about H. Pylori Gastrointestinal Infections

June 2013
A2A Receptor Antagonists and Parkinson’s Disease Treatment

May 2013
Another Setback for Trophic Factor Treatment in Parkinson's Disease

April 2013
IPX066 and What Patients Really Want in New Carbidopa/Levodopa (Sinemet) Formulations

March 2013
The Weather Forecast for Parkinson’s Disease Calls for Worldwide Economic Storm

February 2013
Defeating the Barriers to Implementing Exercise Regimens in Parkinson’s Disease Patients

January 2013
When should you start medication therapy for Parkinson’s disease?

December 2012
Neurologist Care Reduces Hospitalizations in Parkinson's Disease

November 2012
A Victory in Court for Parkinson's Disease Patients who Require Ongoing Rehabilitative Therapies

October 2012
Given the recent FDA announcement about Mirapex (pramipexole), should I be worried about dopamine agonists?

September 2012
What about the new Parkinson’s Disease Vaccine? What should I know?

August 2012
Caffeine as a Potential Treatment for Parkinson’s Disease

July 2012
Time to Consider GPi DBS for Parkinson’s Disease: A Shift in the Practice of Patient Selection for DBS

June 2012
A New Treatment for Parkinson’s Disease-Related Constipation

May 2012
Too Many Pills: Improving Delivery Systems for Parkinson’s Disease Drugs

April 2012
Measuring Quality and Assessing Depression in Parkinson's Disease

March 2012
Watch out for Unexpected Obstacles if You Use a Cueing Strategy to Break Freezing of Gait in Parkinson’s Disease

February 2012
Pill Color, Generic Medications and Insurance Issues: Important Medication-Related Tips for the Parkinson’s Disease Patient

January 2012
Are Blood Tests for Parkinson’s Disease on the Horizon?

December 2011
Placing Stem Cells in Animal Models of Parkinson’s Disease: Another Important Step

November 2011
Important News for the Parkinson’s Disease Community: More Evidence that Sinemet and Madopar are Not Toxic and do Not Accelerate Disease Progression

October 2011
The Case for All Parkinson’s Disease Patients to be Co-managed by a Primary Care-Neurologist Team

September 2011
Scientists say Research on Brain Proteins Involved in Parkinson’s Disease is “Shaping” Up

August 2011
Who Actually Takes Care of Most of the Parkinson’s Patients Worldwide: The Need for Education and the Parkinson’s Toolkit

July 2011
If you are Dizzy or Passing Out, it could be Your Parkinson’s Disease or Parkinson’s Disease Medications

June 2011
How Will Group Visits for Parkinson’s Disease Fit into the Future of Parkinson’s Disease Care?

May 2011
Why Patients Should be Wary of Chelation Therapy for Parkinson’s Disease

April 2011
Opening the Door to Gene Therapy in Parkinson’s Disease: The Need for Refinement of the Technology and Approach

March 2011
Does it Matter if I Can’t Get Brand Sinemet?

February 2011
Should I get a DaTscan or PET scan to confirm my diagnosis of Parkinson’s disease?

January 2011
A Critical Reappraisal of the Worst Drugs in Parkinson’s Disease

December 2010
Environmental Risks for PD: Manganese, Welding, Mining, and Parkinsonism

November 2010
Calling for the FDA to Revise the Eight Sinemet a Day Rule

October 2010
Dry Cleaning Solvents and Potential Environmental Risks for Developing Parkinson’s Disease

September 2010
Maintaining the Balance: Why Parkinson’s Disease Patients Need to Understand Drug Recalls, Withdrawals, and Safety Alerts

August 2010
Shining a Light on Parkinson’s Disease: Optogenetics Has a Bright Future in Research

July 2010
Poor Medication Management of Parkinson's Disease During Hospital Admissions: Patients and Families Can Improve Their Hospital-Based Management

June 2010
Why Are Patches and Continuous Release Technology a Big Deal to Parkinson's?

May 2010
Is the PD SURG Trial Another Surge Forward for DBS Therapy?

April 2010
Cycling in PD in Those Who Can’t Walk: Is it Possible?

March 2010
New iPS Stem Cells for PD: What Does it Mean?

February 2010
Time for Comprehensive Care Networks for PD

January 2010
Is Parkinson's Disease a Prion Disease?

December 2009
Parkinson's Disease Linked to Gaucher's Disease

November 2009
Brain Cells Keep Time Stamps: Implications for Parkinson's Disease Therapies

October 2009
Is it Safe to Have an MRI with a DBS in Place?

September 2009
Take Care of Your Bones as They Are Affected in Parkinson's Disease (Even in Men)

August 2009
Is it Time to Start Paying Attention to Pain Symptoms in Parkinson's Disease Patients?

July 2009
Glutathione Fails to Demonstrate Significant Improvement in PD Symptoms

June 2009
Keeping an Eye on Trials Important to the Parkinson's Disease Patient

May 2009
Increased Risk of Melanoma in Parkinson's Disease

April 2009
Finally a DBS Expert Consensus Statement Aimed at Their True Customers: The Patients

March 2009
Pesticides and Environmental Exposure in Parkinson's disease: Should We Stay Away From the Stink Truck?

February 2009
Is Exercise Effective Treatment and Protection Against PD?

January 2009
Why are Transplant Trials Struggling to Succeed in the Treatment of PD?

December 2008
Are Monoamine Oxidase Inhibitors Disease Modifying or Neuroprotective in PD?

November 2008
Update on Gene Therapy for Parkinson's Disease

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Each month, we will feature a new column by NPF's National Medical Director, Dr. Michael Okun, on the latest developments in Parkinson's disease research. Read the latest "What's Hot in PD?" below.

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