Mitochondrial ND5 Mutations in Idiopathic Parkinson’s Disease

W. Davis Parker, Jr., M.D.

University of Virginia

Grant Program:

Clinical Neuroscience Research

Funded in:

June 2007, for 3 years

Funding Amount:


Lay Summary

Mitochondrial ND5 Mutations in Idiopathic Parkinson's Disease

Scientists still do not know what causes Parkinson’s disease (PD), the progressive degenerative brain disease produced by the death of neurons that use the neurotransmitter dopamine to communicate. Diagnosing PD in symptomatic patients, and differentiating it from other disorders that produce similar symptoms, currently is based on use of PET and SPECT imaging to identify dopamine cell degeneration in a part of the brain called the substantia nigra.  Recently, University of Virginia researchers developed preliminary evidence that PD may involve mutations in certain “mitochondrial” genes. These genes produce proteins that are integral to converting food into energy for cells. Furthermore, these genetic mutations might be identifiable in blood samples.  The investigators will compare blood samples of patients with PD to those of healthy volunteers.  They will determine whether blood samples reveal a specific genetic defect in PD patients.  If so, this will lead to use, for the first time, of a simple blood test for diagnosing PD and identifying those who are genetically at-risk for developing the disease.   The research also is expected to confirm a genetic basis for PD.


Determining the cause of PD and simplifying its diagnosis, are major scientific challenges. PD is characterized by a loss of dopamine-transmitting cells. Patients have slowed speech and movement, tremor, rigid muscles, and balance disturbances.  Many also develop cognitive deficits. Since symptoms of PD are similar to those produced by diffuse Lewy Body dementia, progressive supranuclear palsy, and multiple system atrophy, clinicians use PET and SPECT imaging to make the differential diagnosis. This determination is vital, since L-DOPA treatment is usually effective in PD but not the other diseases.

While the cause of PD remains elusive, research suggests that the death of cells that transmit dopamine involves problems with mitochondria (bodies outside the cell’s nucleus that convert food into energy).  Mitochondrial genes create enzymes, including “complex I,” which catalyze this metabolic conversion. (Mitochondrial genes are passed from mothers to their sons and daughters, but only the daughters pass them on to their children.)   The investigator, in prior studies, found that people with PD have decreased complex I enzyme activity. Moreover, animal model studies by others indicate that PD-like symptoms occur when this enzyme is targeted by the synthetic heroin derivative called “MPTP,” and by the organic gardening pesticide “rotenone.”

Dr. Parker hypothesizes that mutations in mitochondrial genes rather than chromosomal genes might account for the “sporadic” nature of PD which doesn’t typically run in families.  He tested this hypothesis by transferring mitochondrial genes from PD patients into cultured human cells and found that he reproduced the mitochondrial problems seen in PD and reproduced many of the important pathological features of PD such as Lewy bodies.  He studied these genes in PD and control brain tissues and found that PD brain almost always had mutations in a specific region of a single mitochondrial complex I gene and that these mutations affect the cells’ conversion of food into energy.  Further, he hypothesizes, these mitochondrial gene mutations can be found in blood samples of patients with PD.  According to Dr. Parker, therefore, these gene mutations are likely to be a PD biomarker, and may represent the primary genetic defect producing PD.  He will test this hypothesis further by studying this gene in PD and control blood cells.  A total of 75 PD patients will participate. If the researcher’s hypothesis is correct, the PD tissue samples will reveal mutations in mitochondrial gene regions that are responsible for producing the enzyme complex I that is essential for converting food into energy.

Benefits and Challenges

The research poses few challenges, because the investigators have developed and used all necessary laboratory techniques.  The challenge will be in seeing whether the results support their hypothesis.  If not, the negative findings will indicate that the answer lies elsewhere.  If correct, however, the study is expected to result in a simple blood test to diagnose PD, identify those at risk, and lead to new avenues of therapy targeting the genetic mutation and its effects. Additionally, positive results would enhance efforts to identify mitochondrial gene mutations involved in PD, providing new genetically-based therapeutic targets and strategies.    Finally, positive results in this study will support the concept of mitochondrial gene mutations as an important general mechanism in other sporadic diseases.


Mitochondrial ND5 Mutations in Idiopathic Parkinson's Disease

Parkinson's disease occurs sporadically within a population in the vast majority of cases.  This disease is characterized by a systemic loss of complex one activity of the mitochondrial electron transport chain.  This enzyme defect is probably pathogenic and arises from mitochondrial DNA as shown by gene transfer experiments.  Extensive investigation of all seven mitochondrial complex one genes indicated that very low abundance, amino acid changing mutations in a small region of a single gene, ND5, segregate Parkinson's disease tissue from controls.  This project will investigate whether or not these same mutations can be demonstrated in Parkinson's disease and control blood cells.

Investigator Biographies

W. Davis Parker, Jr., M.D.

Dr. Parker is the Eugene P. Meyer Professor of the Neurosciences, Professor of Neurology, and Professor of Pediatrics at the University of Virginia School of Medicine.  He received his undergraduate degree from the Johns Hopkins University and his MD from the University of South Florida.  He has completed residency training in pediatrics and neurology and fellowships in clinical genetics and metabolic disease.  He practices clinical neurology at UVA.  His laboratory focuses on the role of mitochondria in causing human disease.  He has particularly advanced the hypothesis that many apparently non-genetic, sporadic diseases such as Parkinson’s Disease are actually genetic but are inherited via the mitochondrial genome rather than via chromosomes as is the case with the vast majority of genetic disorders.