BioWorld International Correspondent
LONDON - The discovery that some people with an inherited form of Parkinson's disease have mutations in a protein found in mitochondria has opened up a gateway that might lead to treatments for the disease.
A multinational study carried out by teams from 14 research centers in five countries pinpointed a gene called PINK1, and its protein appears to protect cells from stress. In those affected by an extremely rare familial form of Parkinson's disease, that gene is mutated and its protein no longer has the protective effect.
Nick Wood, professor of clinical neurology and neurogenetics at the Institute of Neurology in London and one of the senior authors of the study, told BioWorld International: "It had never been suggested before that this protein was involved as a cause of Parkinson's disease. This finding can almost certainly open avenues leading to new therapeutics and the discovery of new drug targets, although at the moment it is unclear the precise direction these will take."
The challenge now will be understanding what the normal function of PINK1 is, what effect the mutations have on its normal function and how that leads to Parkinson's disease, Wood said.
An account of the study is published online in the April 15, 2004, edition of Sciencexpress in a paper titled "Hereditary Early Onset Parkinson's Disease Caused by Mutations in PINK1."
Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease, affecting between 1 percent and 2 percent of people more than the age of 60. It is caused by loss of the dopamine-manufacturing neurons that originate in the substantia nigra of the brain.
Most cases of Parkinson's disease are sporadic. However, the disease rarely runs in families. Researchers have been keen to identify the gene or genes responsible for those familial cases in the hope that that will provide clues to the pathogenesis of the disease in the common sporadic cases.
The multinational consortium studied a large consanguineous family from Sicily, Italy, in which Parkinson's disease was inherited, and in 2001 mapped a locus, which they called PARK6, to part of chromosome 1. Later, investigation of two further consanguineous families affected by the disease, one from Spain and one from central Italy, also suggested that the PARK6 locus was inherited by those who were affected, but not by those who did not develop the disease.
The paper describes how further studies narrowed the section of interest down to a region containing about 40 genes. Concentrating first on those whose function might be relevant and those expressed in the central nervous system, the researchers began a search for mutations in the affected members of the three families.
They found two mutations in the gene called PTEN-induced putative kinase 1, or PINK1.
All the people affected by Parkinson's disease in the families had inherited two copies of their family's mutation, while all those not affected had at least one normal copy of PINK1. A check on 400 control chromosomes, including 200 from Sicilian individuals, found neither of the mutations.
The mutation in the Spanish family led to a missense mutation, while in the two Italian families that resulted in the protein being 145 amino acids shorter than normal.
Earlier research had shown that PINK1 was expressed throughout the body. Further experiments carried out by Wood and his collaborators showed that the PINK1 protein was found in the mitochondria of cells. They also showed that mutant PINK1, unlike normal copies of the protein, was unable to protect the cells from undergoing apoptosis when a chemical that normally induces apoptosis was added to the cell culture. Similarly, the mitochondria in cells transfected with mutant PINK1 were unable to respond as well following the addition of the chemical as those in normal cells.
The authors write: "Overall, these preliminary findings suggest that wild-type PINK1 may protect neurons from stress-induced mitochondrial dysfunction and stress-induced apoptosis and that this effect is abrogated by the . . . mutation."
Wood said it now will be important to find out what proportion of cases of Parkinson's disease can be explained by mutations in PINK1. The collaborators also plan to investigate the gene's function by making an animal model that lacks PINK1 and one that carries the mutated form of the gene.