PINK1 Research from London

Why do dopamine cells die?

Here's the problem, we read all of these articles and abstracts and try to make some sense of them but sometimes we find our eyes crossing as the confusion and profusion of terminology mounts. Our goal today is really to talk about the significance of the PINK1 gene and recent research at the Institute of Neurology, London under Dr Andrey G Abramov.

There are several genes which have been identified as being linked to family PD - inherited Parkinson's. Many of these genes "write the code" for the proteins which target the mitochondria. Mutations or misfolding of proteins of PINK1 cause an inherited form of PD identified as an autosomal recessive young onset form of Parkinson's disease. The PINK1 gene is specific to the mitochondria.

Mitochondria = an organelle which is part of a cell - just as an organ is to the body. Some cells have just one while others have thousands.
They power the cell by generating chemical energy in the form of adenosine triphospate (ATP) by converting food molecules into ATP.
And that's not all they do.
They are involved in maintaining proper chemical balances within the cells. They are also involved in signaling, a cellular form of grad school whereby a less specialized cell becomes more specialized. Those cells get their doctorates when they become pluripotent.

Mitochondrial proteins will vary depending upon the tissue type. In PINK1 the protein is serine/theronine kinease.

The mitochondria has two walls, the inner and the outer membrane. The outer membrane is easily permeable to small molecules such as ions and sugars. Large molecules need to have know the password, or to have the correct garage door opener signal if you prefer, in order to be transported through the outer membrane. And then things start to get tricky.

How does this relate to PD? First the bad news. In their role as chemical balancers, mitochondria must maintain the proper calcium level of the cell. Abnormal calcium levels have shown to be toxic to neurons. When the PINK1 gene was studied it was learned that its loss resulted in an abnormal calcium overload within the mitochondria. This calcium overload causes "the production of a dangerous reactive oxygen species that interfered with the ability of the mitochondria to transport sugar for energy production."

A normal PINK1 would be able to handle a calcium overload as that is part of their function. Once they malfunction, they are prone to making the dopamine neurons more vulnerable and may indeed cause their deaths.The good news is that Dr Andrey Abramov and his co-researchers at the Institute Neurology, London, UK have a better understanding of why certain dopamine neurons die.

reference: Cell Press 3/13/09 Molecular Cell
http://www.eurekalert.org/pub_releases/2009-03/cp-pmm030909.php

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2649444

Pesticide Exposure and Parkinson's Risk

Pesticides and related lifestyle factors, exposure to well water containing ground run-off, farming using pesticides, rural living are repeatedly reported risk factors for Parkinson's disease. There are few family-based studies looked at those relationships. Is there a genetic connection?

In 1992 the results of a study conducted at the University of Calgary were published. It involved 130 residents with neurologist-diagnosed ideopathic Parkinson's and 260 controls to determine whether agricultural or occupational use of pesticides had an association with increased PD risk. The study looked at field crop farming, grain farming, herbicide or insecticide usage and exposure variables. The ultimate conclusions were that there was a dose-response relation to the PD risk through field and grain crop farming and also occupational use of herbicides.

In 1998 the results of a study by the Department of Neurology at the Henry Ford Health System in Detroit performed a similar study adding cigarette smoking to the mix. The conclusions were similar: a significant association of occupation-exposure (farming) and herbicides and insecticides but no increased risk of PD with rural or farm residence or well water usage. They concluded that farming or pesticide exposure alone did not appear to be a risk factor.

A study was published in the June 2006 issue of Movement Disorders by Dr Demetrius "Jim" Maraganore, Mayo Clinic Professor of Neurology whose principle research interest is to identify the causes of Parkinson's disease, through molecular genetic and epidemiologic approaches. That study confirmed conclusions of prior studies, "What we think may be happening is that pesticide use combines with other risk factors in mens environment or genetic makeup, causing them to cross over the threshold into developiing the disease." Moreover, "One possibility is that to get Parkinson's disease, you not only have to be exposed to pesticides, but you have to be genetically predisposed" He also noted that pesticide exposure accounts for only 10-15% of Parkinson's cases.

In the Mayo Clinic study, investigators contacted all of the Olmsted County, MN residents who had been diagnosed with PD between 1976 and 1995. They were then assigned control matches. The phone interview was to determine the exposure to chemical products: farming, non-farming work or hobbies. Although unable to determine the exact exposure levels the study did conclude that men with PD had 2-4 times more exposure to pesticides than the controls.

In 2006 research at the University of North Dakota, at Emory University and at Harvard University had similar conclusions that pesticide exposure appears to cause a loss of neurons in particular areas of the brain.

Researcher's at Duke University Medical Center and the University of Miami Miller School of Medicine examined 319 cases and 296 relative and other controls. They recorded associations of direct pesticide application, well-water consumption, and farming residences/occupations. They controled for age at examination, sex, cigarette smoking and caffeine consumption.

Individuals with PD were significantly more likely to report direct pesticide application than their unaffected relatives. Associations of direct pesticide application did not vary by gender.
When classifying pesticides by a functional type, both insecticides and herbicides were found to significantly increase the risk of PD: Two specific classes of insecticides, organochlorines and organophosphorus, were significantly associated with PD.

Sources:
Pesticide exposure and risk of Parkinson's disease:
A family-based case-control study
Hancock,Martin,Mayhew etal 8 March, 2008
Duke University Medical Center
University of Miami Milleer school of Medicine

http://www.voanews.com/english/archive/2006-06/2006-06-24-voa21.cfm
http://www.ncbi.nlm.nih.gov/pibmed/9595985
http://www.ncbi.nlh.gov/pubmed/17708091?ordinalpos=1&tool=EntrezSystem2.PEnt
http://www.ncbi.nlm.nih.gov/sites/entrez

To view Purple Haze, Pesticides, Big Brother and the Migrant Farm Worker as referenced in the comment section:
http://www.phf.org/infrastructure/resources/marphli/purple.pdf

Improving the Aging Cellular Disposal System

Dr. Ana Maria Cuervo, associate professor at Albert Einstein Medical College in New York, NY, conducted an experiment that improved the natural cellular garbage disposal system in mice which made old liver cells act young again. Someday this may be possible with brain cells as well.

This system removes 30% of the cells' damaged proteins, taking them to inner cell structures called lysosomes, organelles of the cell containing digestive enzymes which break down the proteins. Studies show that the disposal system doesn't work as well when it gets older. This is caused by a loss of receptors on the surface of the lysosomes that causes a buildup of damaged proteins in the cell.

For the experiment, Dr. Cuervo created mice with an extra gene for the lysosomes receptors. The extra gene was added only to the liver cells and was turned on only when the mice reached middle age. When the mice were examined at the equivalent to 80 years for a human, the liver cells were able to maintain the same activity as when they were young. They removed all damaged oxidized proteins.

Dr. Cuervo is working with an animal model of Parkinson's disease "and we hopefully can prevent brain deterioration."

People who have Parkinson's Disease have a genetic mutation that can cause defective proteins later in life. Improving the brain's cellular disposal system may delay that effect.

According to Dr Cuervo they are trying to identify compounds that do the same thing. They are also looking at dietary manipulation. Modification of the diet might also prevent this system from deteriorating with age. (Possibly balancing the pH of the lysosomes might be one direction of diet.)

The findings were published in the August 10, 2008 online journal Nature Medicine.

For a quick read and diagram of Lysosomes see: http://en.wikipedia.org/wiki/Lysosome