Is speeding up the key to slowing down Parkinson’s?

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A recent study found that rats treated with the antidepressant nortriptyline had reduced abnormal levels of alpha-synuclein, a protein critical to the development of Parkinson’s disease.  Alpha-synuclein is normally found throughout nerve cells, but in Parkinson’s, this protein abnormally clumps together and forms Lewy bodies.  These Lewy bodies surround and destroy nerve cells, which are responsible for coordinating movements.  As these nerve cells die, patients exhibit hand tremors, limb stiffness and coordination problems.  So what triggers alpha-synuclein to clump together and eventually form Lewy bodies?

Researchers at Michigan State University suggest that speed may be the key.  In healthy brains, alpha-nuclein naturally reconfigures and folds into clusters at a specific speed.  This process is hypothesized to be slower in Parkinson’s, resulting in a toxic buildup of alpha-nuclein.  When the antidepressant nortriptyline was given to a rat model of Parkinson’s, they observed a faster rate of alpha-nuclein reconfiguration, resulting in less abnormal levels of alpha-nuclein in the brain.

While the choice of an antidepressant to treat Parkinson’s may seem unusual, this was, in fact, intentional. The authors previously examined newly-diagnosed Parkinson’s disease patients, and studied how well they fared in clinical trials.  Surprisingly, patients taking antidepressants were less likely to need additional drug therapy.  This suggested that antidepressants could help slow the progression of Parkinson’s.   Based on their recent study in rats, antidepressants appear to slow the development of Parkinson’s by speeding up the reconfiguration of alpha-nuclein.

While the current study didn’t test motor coordination in the rats treated with nortriptyline, it will be important for future studies to examine.  In addition, nortriptyline did not affect rats with existing abnormal levels of alpha-nuclein.  This suggests that nortriptyline may be most effective when administered during the early development of the disease.  Still, nortriptyline has a long history of safety and efficacy, which makes it a promising therapeutic to test in a clinical setting.

Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form

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