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Parkinson’s disease

When neurons lose a protective protein

Munich, 05/20/2008

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. PD patients suffer from motors symptoms, including a slowing of movements and difficulties in initiating movements, tremor and muscle rigidity. Non-motor symptoms may also occur, such as depression or dementia. The symptoms of PD are primarily caused by the loss of specific neurons in a distinct part of the midbrain called substantia nigra. These nerve cells produce dopamine, an important neurotransmitter. Over the past decade, several genes have been identified which are responsible for familial forms of PD. One of the PD genes is parkin, for which more than 100 disease-causing mutations have been described. A research team under the lead of Dr. Konstanze F. Winklhofer at  Ludwig-Maximilians-Universität (LMU) München has previously shown that the parkin protein has a wide neuroprotective capacity and protects neurons from stress-induced cell death. Winklhofer and her colleagues have now addressed the question of how mutations in the parkin gene can lead to a loss of parkin function. In the recent issue of “The Journal of Biological Chemistry” they show that some mutations in the parkin gene interfere with the correct folding of the parkin protein, leading either to the accumulation of aggregated parkin or to its accelerated degradation. As a consequence, less functional parkin protein is available to protect neurons from cell death.

The majority of PD cases occur sporadically, with aging being the most important risk factor, however, the mechanism underlying the death of dopamine-producing neurons still remains elusive. ”The identification of genes which are responsible for familial forms of PD was a milestone in PD research, because insight into the function of PD-associated genes helps to understand molecular pathways implicated in the disease process,” says Winklhofer. “This is a prerequisite to develop novel therapeutic strategies, which may delay or halt the progressive degeneration of neurons.” In their latest study the scientists show that pathogenic mutations in the parkin gene can cause a misfolding of the parkin protein. To fulfill their designated functions, proteins have to adopt a specific three-dimensional structure in a process called protein folding. Some mutations in the parkin gene interfere with this process, resulting either in the accumulation of misfolded parkin protein within neurons or in its enhanced degradation.

Previous studies revealed that parkin can protect dopaminergic neurons against various stress conditions, such as oxidative stress or mitochondrial dysfunction. Thus, the inactivation of parkin by misfolding shuts down a protective pathway, leading to an increased vulnerability of dopaminergic neurons to stress conditions. ”So far, we don’t know whether these events occur in patients and whether they might be a target for therapeutic interventions,” says Winklhofer. “But it’s interesting that parkin can be inactivated by different mechanisms. We can speculate now that different genetic mutations cause different types of misfolding or that they influence parkin at different phases of the folding process. Another important question is why dopamine-producing neurons are more vulnerable to a loss of parkin function than other neuronal cells.”

 

Publication:
“Aberrant Folding of Pathogenic Parkin Mutants – Aggregation versus Degradation“,
Julia S. Schlehe, A. Kathrin Lutz, Anna Pilsl, Kerstin Lämmermann, Katja Grgur, Iris H. Henn, Jörg Tatzelt and Konstanze F. Winklhofer,
The Journal of Biological Chemistry, May 16, 2008

 

Contact:
Konstanze F. Winklhofer, M.D., Ph.D.
Adolf-Butenandt-Institut at LMU Munich
Tel.: +49-89-2180 - 75483
Fax: +49-89-2180 - 75415
E-Mail: konstanze.winklhofer@med.uni-muenchen.de
Web: http://haass.web.med.uni-muenchen.de/Research/NBC/Winklhofer

 

 

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