Posts tagged parkinson’s disease

Researchers at the MRC Laboratory of Molecular Biology in the United Kingdom have determined the crystal structure of Parkin, a protein found in cells that when mutated can lead to a hereditary form of Parkinson’s disease. The results, which are published in The EMBO Journal, define the position of many of the mutations linked to hereditary Parkinson’s disease and explain how these alterations may affect the stability and function of the protein. The findings may in time reveal how the activity of Parkin is affected in patients with this rare but debilitating type of Parkinson’s disease.

Parkinson’s disease is a progressive neurodegenerative disease that affects more than seven million people worldwide. Most cases of the disease occur in older individuals and are sporadic (non-familial), but around 15% of patients develop symptoms early in life because of inherited mutations in a limited number of disease genes. Why Parkin mutations are especially detrimental in nerve cells is not fully understood, but previous research indicates that Parkin regulates the function of mitochondria, the organelles that generate energy in the cell. Some disease mutations in the PARKIN gene can be easily explained since they lead to loss or instability of the Parkin protein, but many others are more difficult to understand.

Around 50% of cases of familial recessive Parkinson’s disease are caused by mutations in the PARKIN gene, which encodes a protein that belongs to the RBR ubiquitin ligase enzyme family. Enzymes in this family couple other proteins in the cell to a molecule called ubiquitin, a step that can alter the function or stability of these target proteins. To understand how Parkin and other RBR ubiquitin ligase enzymes achieve this, EMBO Young Investigator David Komander and his coworker Tobias Wauer crystallized a form of human Parkin and used X-ray diffraction patterns to determine how the Parkin protein chain folds into a three-dimensional structure. Their experiments revealed an in-built control mechanism for Parkin activity, which is lost in the presence of some of the mutations responsible for Parkinson’s disease. Wauer and Komander pinpointed amino acids of Parkin with key functions in ubiquitin ligase activity that are sensitive to blocking by reagents previously characterized in their laboratory. “This sensitivity to inhibitors that were developed for a very different class of enzymes is particularly exciting,” Komander remarked. “We could also show that these inhibitors affect related RBR ubiquitin ligases such as HOIP, which is important for inflammatory immune responses.”

The crystal structure of Parkin is already revealing some of the secrets of this molecule, which under the right conditions can protect cells from the damage that arises during Parkinson’s disease. “In time the structure may also allow development of other compounds that alter Parkin activity, which could serve as ways to limit the progression and impact of Parkinson’s disease,” concluded Komander.

(Source: embo.org)

Research opens door to new drug therapies for Parkinson’s disease

McGill University researchers have unlocked a new door to developing drugs to slow the progression of Parkinson’s disease. Collaborating teams led by Dr. Edward A. Fon at the Montreal Neurological Institute and Hospital -The Neuro, and Dr. Kalle Gehring  in the Department of Biochemistry at the Faculty of Medicine, have discovered the three-dimensional structure of the protein Parkin. Mutations in Parkin cause a rare hereditary form of Parkinson’s disease and are likely to also be involved in more commonly occurring forms of Parkinson’s disease. The Parkin protein protects neurons from cell death due to an accumulation of defective mitochondria. Mitochondria are the batteries in cells, providing the power for cell functions. This new knowledge of Parkin’s structure has allowed the scientists to design mutations in Parkin that make it better at recognizing damaged mitochondria and therefore possibly provide better protection for nerve cells. The research will be published online May 9 in the leading journal Science.

VIDEO: Parkin protein

“The majority of Parkinson’s patients suffer from a sporadic form of the disease that occurs from a complex interplay of genetic and environmental factors which are still not fully understood, explains Dr. Fon, neurologist at The Neuro and head of the McGill Parkinson Program, a National Parkinson Foundation Centre of Excellence. “A minority of patients have genetic mutations in genes such as Parkin that cause the disease. Although there are differences between the genetic and sporadic forms, there is good reason to believe that understanding one will inform us about the other. It’s known that toxins that poison mitochondria can lead to Parkinson’s-like symptoms in humans and animals. Recently, Parkin was shown to be a key player in the cell’s system for identifying and removing damaged mitochondria.”

Dr. Gehring, head of McGill’s structural biology centre, GRASP, likens Parkin to a watchdog for damaged mitochondria. “Our structural studies show that Parkin is normally kept in check by a part of the protein that acts as a leash to restrict Parkin activity. When we made mutations in this specific ‘leash’ region in the protein, we found that Parkin recognized damaged mitochondria more quickly. If we can reproduce this response with a drug rather than mutations, we might be able to slow the progression of disease in Parkinson’s patients.”

Parkin is an enzyme in cells that attaches a small protein, ubiquitin, to other proteins to mark them for degradation. For example, when mitochondria are damaged, Parkin is switched on which leads to the clearing of the dysfunctional mitochondria. This is an important process because damaged mitochondria are a major source of cellular stress and thought to play a central role in the death of neurons in neurodegenerative diseases.

Husband and wife team, Drs. Jean-François Trempe and Véronique Sauvé, are lead authors on the paper. Dr. Sauvé led the Gehring team that used X-ray crystallography to determine the structure of Parkin. Dr. Trempe in the Fon laboratory directed the functional studies of Parkin.

(Source: mcgill.ca)

Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinson’s disease, the progressive movement disorder. The discovery highlights potential new therapeutic targets for Parkinson’s and could lead to a blood test for the disease. The study, based mainly on analysis of human brain tissue, was published in the online edition of Nature Communications.

Studies of rare, familial (heritable) forms of Parkinson’s show that a protein called alpha-synuclein plays a role in the development of the disease.  People who have extra copies of the alpha-synuclein gene produce excess alpha-synuclein protein, which can damage neurons. The effect is most pronounced in dopamine neurons, a population of brain cells in the substantia nigra that plays a key role in controlling normal movement and is lost in Parkinson’s.  Another key feature of Parkinson’s is the presence of excess alpha-synuclein aggregates in the brain.

As the vast majority of patients with Parkinson’s do not carry rare familial mutations, a key question has been why these individuals with common sporadic Parkinson’s nonetheless acquire excess alpha-synuclein protein and lose critical dopamine neurons, leading to the disease.

Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinson’s. “It turns out multiple different alpha-synuclein transcript forms are generated during the initial step in making the disease protein; our study implicates the longer transcript forms as the major culprits,” said study leader Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and neurology at CUMC. “Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinson’s. In our study, we show that people with ‘bad’ variants of the gene make more of the elongated alpha-synuclein transcript forms. This ultimately means that more of the disease protein is made and may accumulate in the brain.”

“An unusual aspect of our study is that it is based largely on detailed analysis of actual patient tissue, rather than solely on animal models,” said Dr. Abeliovich. “In fact, the longer forms of alpha-synuclein are human-specific, as are the disease-associated genetic variants. Animal models don’t really get Parkinson’s, which underscores the importance of including the analysis of human brain tissue.”

“Furthermore, we found that exposure to toxins associated with Parkinson’s can increase the abundance of this longer transcript form of alpha-synuclein. Thus, this mechanism may represent a common pathway by which environmental and genetic factors impact the disease,” said Dr. Abeliovich.

The findings suggest that drugs that reduce the accumulation of elongated alpha-synuclein transcripts in the brain might have therapeutic value in the treatment of Parkinson’s. The CUMC team is currently searching for drug candidates and has identified several possibilities.

The study also found elevated levels of the alpha-synuclein elongated transcripts in the blood of a group of patients with sporadic Parkinson’s, compared with unaffected controls. This would suggest that a test for alpha-synuclein may serve as a biomarker for the disease. “There is a tremendous need for a biomarker for Parkinson’s, which now can be diagnosed only on the basis of clinical symptoms. The finding is particularly intriguing, but needs to be validated in additional patient groups,” said Dr. Abeliovich. A biomarker could also speed clinical trials by giving researchers a more timely measure of a drug’s effectiveness.

(Source: cumc.columbia.edu)