The research is published by Cell Press in the March 13th issue of the journal Molecular Cell .

PD is a neurodegenerative disease characterized by a specific loss of dopamine neurons. Several genes have been linked with inherited forms of PD. Many of these genes encode proteins that are targeted to mitochondria, tiny intracellular "power plants" that metabolize oxygen and generate energy. Mitochondria also play a major role in maintaining appropriate calcium levels inside of cells. Abnormal calcium levels can be toxic to neurons and are associated with a range of neurodegenerative diseases.

Mutations in the PINK1 gene cause an inherited form of PD and research has shown that PINK1 is localized to mitochondria. "We previously demonstrated that PINK1 deficiency results in an age related loss of neuronal viability, and an increased sensitivity to mitochondrial dysfunction. However, the mechanisms underlying this mitochondrial pathophysiology remained unknown," explains senior study author Dr. Andrey Y. Abramov from the Institute of Neurology in London.

Dr. Abramov and colleagues used a sophisticated and dynamic imaging technique to explore the mitochondrial pathophysiology of PINK1-dependent PD. They found that loss of PINK1 resulted in an aberrant calcium overload inside the mitochondria. This overload stimulated production of dangerous reactive oxygen species that interfered with the ability of the mitochondria to transport sugar needed for energy production. This phenomenon could be reversed by providing substrates for energy production. "These data strongly suggest that the respiratory complexes in PINK1 deficiency are still intact and that their functional inhibition is in fact secondary to reduced substrate supply," offers Dr. Abramov.

Importantly, adult dopamine-producing neurons are frequently exposed to large influxes of calcium that must be buffered by the mitochondria. Mitochondria dysfunction and an inability to process these calcium loads are likely to make the dopamine neurons quite vulnerable to injury "Our findings define a mechanism whereby PINK1 dysfunction may cause the death of dopamine neurons," concludes Dr. Abramov.

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Some alleles are detrimental to health. Most of these are recessive, meaning that they do not cause problems unless the organism inherits two copies of them - one from each parent. When the alleles differ, one (the dominant allele) often masks the deleterious effects of the other.

But the interaction of parental alleles in their offspring can be quite complex. Sometimes an allele causes a disease or disorder even if it is paired with a different allele. Sometimes several genes influence a single trait. And sometimes two different alleles can lead to a higher level of gene activity than occurs in either parent (this last phenomenon is called overdominance).

When closely related individuals mate, their offspring are likely to end up with identical alleles for many traits. Many potentially harmful recessive alleles are no longer masked by dominant alleles, so more genetic disorders arise. Similarly, offspring that inherit two identical alleles for some traits will also lose any advantages once conferred by overdominance.

Biologists have long wondered which of these mechanisms causes the reproductive failures seen in inbred populations. "It's still being debated," Paige said.

The new study found that about 75 percent of the reproductive declines seen in the inbred flies could be attributed to the loss of dominant alleles and the subsequent "unmasking" of deleterious alleles. More surprisingly, the data also indicated that 25 percent of the declines were due to the loss of overdominance.

"That means we have two mechanisms ongoing," Paige said. "One does predominate, but the other may be important, too."

The fact that a relatively large number of genes are affected by inbreeding is bad news for conservationists hoping to save small populations of plants or animals from extinction, Paige said.

It means that there is no easy fix to the problem of inbred populations. The best approach is to try to preserve and maintain genetic diversity in natural populations well before they begin their slide into an "extinction vortex," he said.

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