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.”
“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
Konstanze F. Winklhofer, M.D., Ph.D.
Adolf-Butenandt-Institut at LMU Munich
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