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Scientists Discover Key Process that Contributes to Common Form of Parkinsonís

New research identifies a molecular pathway — the polyamine pathway — that may explain how Parkinson’s disease (PD) develops in people who have no family history of the disease.  The results appear in the September 13 early online issue of Proceedings of the National Academy of Sciences.

 Understanding the causes of Parkinson’s at the molecular level is a first step toward finding targets for new drug therapies.  In the last decade scientists have identified genetic mutations that underlie Parkinson’s in a small percentage of people with the disease.  They have begun to unravel what goes awry at the molecular level in these unusual cases.  This has given them an opening into understanding the molecular pathways involved in PD more generally.  In particular, as a result of genetic studies, researchers now recognize the importance of the protein known as alpha-synuclein, which accumulates — with toxic effects — in certain brain cells of people with PD.

 The authors of the new study, led by Scott A. Small, M.D., at Columbia University College of Physicians and Surgeons with funding in part from the Parkinson's Disease Foundation (PDF), set out to identify a molecular pathway involved in the common, or classic, form of PD.  They used a recently available technique called gene expression profiling to compare which genes were “switched” on or off in cells from two adjacent areas of the brain stem, one affected by PD, the other not.  They did the analysis on postmortem brain cells from people both with and without Parkinson’s.

They looked for molecular pathways which were impaired in cells in areas affected by PD that were not impaired in areas unaffected by PD and or in people without PD.  They confirmed their findings by using both animal and human models.

Results

Of the genes switched off, one was a critical enzyme known as spermidine/spermine N1-acetyltransferase 1 (SAT1).  Researchers found that levels of SAT 1 were lower in the brain cells from people with PD than in those without the disease. 

These results allowed the researchers to home in on a molecular pathway known as the polyamine pathway.  SAT1 regulates levels of polyamines, another type of molecule:  the less SAT1, the higher the level of polyamines.   Polyamines, in turn, have been implicated in the accumulation of alpha-synuclein; the above-mentioned protein mentioned that is a hallmark sign of PD.

 Further experiments were needed to connect this pathway with the changes observed in the brain cells of people with PD.  These studies were done in model systems.  The researchers showed in a yeast model that decreasing SAT1, which raised polyamine levels, made alpha-synuclein more toxic to cells.  In experiments with a mouse model of PD, decreasing SAT1 led to more alpha-synuclein in brain cells; while raising SAT1 rescued cells from the effects of alpha-synuclein.  The scientists also investigated whether they could find mutations in the SAT1 gene in people with PD.  They sequenced the gene in nearly 500 people with PD and a similar number of healthy research subjects.  A variant of SAT1 was discovered in a small percentage — less than 1 percent — of the people with PD.

What Does It Mean?

The finding of an association between high polyamine levels and PD – if confirmed – may have two potentially important clinical implications.  First, polyamines may serve as a biological marker for PD.  Since polyamines can be measured in blood and in cerebral spinal fluid, they may serve as tests for early detection of PD, and for monitoring the effectiveness of therapies.  Currently, no such blood or spinal fluid tests are available. 

In addition, lowering polyamines levels in nerve cells was suggested by the authors as a novel approach to modifying PD.  Since the enzyme SAT1 can lower polyamines levels drugs that boost its activity may be useful against PD.  Studies to determine whether any of these drugs can cross the blood-brain barrier, one of the first steps in investigating the possibility of using them, are just beginning.  In addition, although elevated brain levels of polyamines were linked to PD in the recent report, further research is needed to determine whether reducing polyamines in fact lessens PD symptoms or slows disease progression.

 

Reference: Lewandowski NM, Ju S, Verbitsky M, Ross B, Geddie ML, Rockenstein E, Adame A, Muhammad A, Vonsattel JP, Ringe D, Cote L, Lindquist S, Masliah E, Petsko GA, Marder K, Clark LN, Small SA. Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16970-5. Epub 2010 Sep 13. (www.ncbi.nlm.nih.gov/pubmed/20837543)

 

Source Date: Sep 13 2010