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Parkinson’s Disease: More Signs of Mitochondrial Damage and Hope for Repair


For release: Wednesday, December 8, 2010

Neurons require vast amounts of energy, and are filled with hundreds of mitochondria.

New research supports a theory that cellular energy factories called mitochondria play a central role in Parkinson’s disease.  Moreover, drugs capable of jumpstarting mitochondria, including one drug currently on the market for diabetes, could help fight the disease.

Parkinson’s disease attacks neurons in a brain region needed for motor control, called the substantia nigra.  The loss of those neurons leads to involuntary shaking, slowed movements, muscle stiffness and other symptoms.  Medications can help control these symptoms, but there is currently no treatment to slow the disease course.

In most cases, Parkinson’s disease is sporadic, meaning its cause is unknown.  However, research has hinted that the disease involves a failure of mitochondria.  Some pesticides have toxic effects on mitochondria, and can induce symptoms of Parkinson’s disease in animals.  Meanwhile, rare forms of Parkinson’s disease are linked to defects in two genes – parkin and PINK1 – that help clear damaged mitochondria from the brain.  (See Researchers Firm up Evidence for Role of Mitochondria in Parkinson’s Disease.) 

Researchers also have detected signs of mitochondrial damage in patients’ brains, but those findings beg the question:  Is the damage a cause or a consequence of the disease?

The new study, published in Science Translational Medicine,1 found that hundreds of genes needed for mitochondrial function are less active in people with Parkinson’s disease.  This was true even in people with “subclinical” Parkinson’s – people who never had clear symptoms of the disease but showed early signs of it on autopsy (such as Lewy bodies, the debris-filled packets that accumulate inside patients’ brain cells).

The study resulted from an international collaboration led by Clemens Scherzer, M.D., neurologist at Brigham and Women’s Hospital and Harvard Medical School in Boston.  The researchers were not looking for mitochondrial defects.  They were casting a wide net for clues to the causes of sporadic Parkinson’s disease, Dr. Scherzer said.

“We were searching for biological pathways that are abnormal in Parkinson’s disease,” he said.

Dr. Scherzer and his colleagues probed gene activity – or expression – in more than 400 tissue samples from patients and healthy controls, collected at labs in the U.S. and Europe.  About one-fifth of the samples were blood; the rest consisted of postmortem brain tissue.  The brain tissue samples included individual neurons that were carefully removed from the substantia nigra with a laser.  This gave the researchers a glimpse of the changes in gene expression that occur in a single neuron as it succumbs to Parkinson’s disease.

The researchers found 10 gene sets (groups of functionally related genes) whose expression was reduced in Parkinson's disease, including subclinical cases.  All 10 gene sets are involved in mitochondrial function.  One set consists of genes under the control of PGC-1alpha, a master gene that regulates energy metabolism and mitochondrial biogenesis.  Biogenesis refers to the production of new mitochondria to replace those that have broken down.

This last finding “suggests a potential drug target,” said Dr. Scherzer.

Some drugs that are used to stabilize blood glucose levels in diabetes appear to act on PGC-1alpha and related pathways.  For example, pioglitazone, a relative of the diabetes drug rosiglitazone, has been shown to stimulate mitochondrial biogenesis.  Based on these observations, pioglitazone or similar drugs might hold promise for restoring mitochondrial function and staving off neuronal loss in Parkinson’s disease, Dr. Scherzer said. 

He and his colleagues tested this idea in cell culture experiments.  When dosed with the pesticide rotenone or the protein alpha-synuclein (found in Lewy bodies), neurons grown in culture become sickly and die much as they do in Parkinson’s disease.  The researchers found they could rescue the cells with extra copies of the PGC-1alpha gene.

The NIH Exploratory Trials in Parkinson's Disease (NET-PD)2 is funding a pilot study to test pioglitazone in patients.

Dr. Scherzer’s study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), both part of the National Institutes of Health.   An NINDS grant funded through the American Recovery and Reinvestment Act (ARRA) provided support for a postdoctoral fellow in Dr. Scherzer’s group.  For more information about research funded by NINDS and ARRA, please visit NINDS Recovery Act Stories.  Additional support came from the Michael J. Fox Foundation, the RJG Foundation, and the M.E.M.O. Hoffman Foundation.  NET-PD is sponsored by NINDS.

- By Daniel Stimson, Ph.D.

1Zheng B et al.  “PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease.”  Science Translational Medicine, October 6, 2010, Vol. 2 (52), pp. 1-14.

2 A phase II trial of pioglitazone in early Parkinson's disease was initiated in March 2011.

Last Modified March 13, 2014