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Discovery of new Parkinson’s disease gene may lead to improved treatments

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UCLA researchers have identified a new gene involved in Parkinson’s disease; the discovery might lead to new treatments, and possibly a cure, for the neurodegenerative disorder. The findings were published on June 4, 2014, in the journal eLife.

The study authors note that Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. No cure is available for the disease, which is diagnosed in approximately 60,000 Americans each year. It is estimated that currently approximately 1 million Americans suffer from the disorder; this number is greater than the number of individuals who are diagnosed with multiple sclerosis, muscular dystrophy and amyotrophic lateral sclerosis (ALS; Lou Gehrig’s disease) combined. Parkinson’s disease is due to the impairment or loss of multiple neurons in the brain over time. The result is symptoms such as movement impairments, including tremor, rigidity, slowness in movement and difficulty walking, as well as depression, anxiety, sleeping difficulties, and dementia, explained study team leader Dr. Ming Guo, an associate professor of neurology and pharmacology and a practicing neurologist at UCLA.

In inherited cases of the disease, a small number of genes have been implicated. The UCLA research team was one of two groups worldwide, which first reported in 2006 in the journal Nature, that two of these genes, PTEN-induced putative kinase 1 (PINK1) and PARKIN, work together to maintain the health of mitochondria. These structures are sometimes described as “cellular power plants” because they generate most of the cell’s supply of adenosine triphosphate (ATP), used as a source of chemical energy. These structures are sometimes described as “cellular power plants” because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. Mutations in these genes lead to early-onset Parkinson’s disease.

The investigators showed that when PINK1 and PARKIN are functioning normally, they help maintain the regular shape of healthy mitochondria and stimulate elimination of damaged mitochondria. The accumulation of unhealthy or damaged mitochondria in nerve cells and muscles eventually results in Parkinson’s disease. In the five-year study, the researchers found that the new gene, called MUL1 (also known as MULAN and MAPL), plays a significant role in facilitating the pathology of the PINK1 and PARKIN. The study, which was conducted on fruit flies and mice, revealed that providing an extra amount of MUL1 reverses the mitochondrial damage due to mutated PINK/PARKIN; in contrast, inhibiting MUL1 in mutant PINK1/PARKIN exacerbates (worsens) the damage to the mitochondria. Furthermore, the investigators found that removing MUL1 from mouse neurons of the PARKIN disease model causes unhealthy mitochondria and degeneration of the neurons.

“We are very excited about this finding,” noted Dr. Guo. She added, “There are several implications to this work, including that MUL1 appears to be a very promising drug target and that it may constitute a new pathway regulating the quality of mitochondria.” She described the study as “a major advancement in Parkinson’s disease research.” She explained, “We show that MUL1 dosage is key and optimizing its function is crucial for brain health and to ward off Parkinson’s disease. Our work proves that mitochondrial health is of central importance to keep us from suffering from neurodegeneration. Further, finding a drug that can enhance MUL1 function would be of great benefit to patients with Parkinson’s disease.”

The next phase of this research for Dr. Guo’s team will be to will test these results in more complex organisms; in so doing, they hope to reveal additional functions and mechanisms of MUL1. In addition, the researchers will conduct small molecule screens to help identify potential compounds that specifically target MUL1. They also will assess whether mutations in MUL1 exist in some patients with inherited forms of Parkinson’s disease.