The damage to cell powerhouses "Mitochondria" leads to Parkinson's disease

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Source: Nature News, published online 6 October 2010 (With modifications)

Parkinson's disease (PD) is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills, speech, and other functions. PD belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, postural abnormalities, gait abnormalities, a slowing of physical movement and a loss of physical movement in extreme cases. Normally this involves insufficient formation and thus action of dopamine produced in the dopaminergic neurons of the midbrain. PD is a devastating condition that gradually robs its victims of muscle control. Its cause is unknown, but a complex mixture of genetic and environmental risk factors is thought to be to blame in many cases.

Recent results, published today in Science Translational Medicine, describing painstaking analysis of more than 400 brain tissue samples has revealed a link between Parkinson's disease and the loss of cellular powerhouses called mitochondria. If packed with additional data, these results could warrant clinical trials of existing drugs (currently used to treat other diseases) that activate a key pathway able to repair and replace broken mitochondria. Furthermore, some patients with a rare, genetically inherited form of Parkinson's disease carry mutations in key genes that regulate mitochondrial function. These findings, together with data linking other neurological illnesses such as Huntington's disease to damaged mitochondria, have fuelled interest in the idea of fixing broken mitochondria as a way to treat the conditions, says Flint Beal, a neurologist at Weill Cornell Medical College in New York who was not involved in the latest study. "Companies are getting more and more interested in mitochondria as a therapeutic target," he says. "It's becoming a popular approach."

But neurologist Clemens Scherzer of Harvard Medical School in Boston, Massachusetts — lead author on the current study — didn't set out to study mitochondria. He and an international consortium of researchers began by profiling patterns of gene expression in diseased versus healthy brains. The team gathered data from roughly ten times more samples than had ever before been analysed in a single Parkinson's disease study, says Scherzer, allowing his team to conduct a more sensitive sweep of gene expression changes.

The analysis for millions of data points yielded ten gene sets not previously associated with Parkinson's disease. All are involved in mitochondrial function and energy generation. Moreover, genes regulated by a single protein called PGC-1α were expressed at abnormally low levels in patients with Parkinson's disease. Increasing the expression of that protein in rat neurons grown in culture was enough to reduce the toxic effects of rotenone. That, says Scherzer, suggests that PGC-1α-activating drugs might stave off the damage to the brain caused by Parkinson's disease. Such drugs have already been widely pursued as potential therapies for type 2 diabetes, and some have already been approved for that use. Avandia (rosiglitazone), a diabetes drug recently pulled from the European market because it raises the risk of heart attack, activates a key protein in the PGC-1α pathway. But a related drug called Actos (pioglitazone) has not been firmly linked to heart attack and remains in use. Beal says that a clinical trial to test Actos in patients with Parkinson's disease has already been approved by regulators.
The gene expression analysis will be a valuable tool for future research, says Asa Abeliovich, a neurologist at Columbia University Medical Center in New York. But it is still unclear whether the PCG-1α pathway is specifically suppressed in Parkinson's disease, or if that suppression is just a consequence of the widespread mitochondrial damage that is provoked when neurons become damaged, he adds.

Nevertheless, if targeting PGC-1α has a beneficial effect in animal models, such details may not matter in the long run. "Is it simply that all mitochondrial function is messed up — which is what it looks like — or is it that PGC-1α specifically is messed up?" he asks. "We don't know. But you could argue, 'Who cares? We're just trying to cure the disease.'"