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Efficient Recycling: How Neurons Dispose of Alpha-Synuclein
- Nov 02 2011
Too much of the protein alpha-synuclein in neurons can predispose people to Parkinson’s Disease (PD). Now a study in the October 12 issue of The Journal of Neuroscience has identified two distinct cellular pathways that help neurons dispose of unwanted alpha-synuclein. These findings might help scientists understand why some people accumulate too much of protein and help identify drugs that speed up its removal.
Just as people recycle paper, plastic and glass from their homes to maintain healthy conditions, cells need ways to dispose of proteins that are faulty, in excess, or simply no longer needed. If for some reason cells cannot keep up with their recycling, abnormally high levels of proteins accumulate. In the case of alpha-synuclein, these high levels increase the likelihood that the protein will clump together, forming the Lewy bodies that characterize Parkinson’s.
Neurons have two major ways to dispose of cellular garbage: the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). The UPS is somewhat like targeted recycling system, one that sorts paper, plastic and glass. In UPS, specific enzymes tag unwanted proteins with a small protein called ubiquitin, which targets them for recycling by a protein complex called the proteasome. In contrast, ALP is more like a general garbage system that collects and recycles all materials in bulk. In ALP the cell engulfs and “digests” unwanted components in an acidic compartment known as the lysosome. Some studies laboratory studies have implicated UPS as the primary pathway for alpha-synuclein removal, whereas other data point toward ALP.
To settle this debate, Darius Ebrahimi-Fakhari, a medical student at the University of Heidelberg in Germany, undertook a Parkinson’s Disease Foundation-funded student fellowship in the lab of Pamela McLean, Ph.D., at the Massachusetts General Hospital. In Dr. McLean’s lab, Mr. Ebrahimi-Fakhari used a state-of-the-art imaging procedure that provides a “window” on a living mouse’s brain. Through a tiny hole in the mouse’s skull, the researchers applied drugs directly to the brain that interfered specifically with UPS or ALP. After 24 hours, they anesthetized the mice and used a special microscope anesthetic called a multiphoton imager to observe levels of alpha-synuclein in the animals’ brains.
- Disrupting UPS increased alpha-synuclein levels, in both normal mice and those genetically engineered to produce abnormally high levels of alpha-synuclein. This suggests that UPS recycles alpha-synuclein, regardless of the protein’s initial levels.
- ALP-inhibiting drugs increased the level of alpha-synuclein in mice that already produced abnormally high levels of the protein, but not in normal mice. This result indicates that although ALP may not normally recycle much alpha-synuclein, the cell can recruit ALP to help dispose of heavy loads of the protein.
- When alpha-synuclein levels are high, disrupting UPS can enhance ALP, and vice versa. The result suggests that UPS and ALP can communicate with each other to control alpha-synuclein levels.
What Does It Mean?
Excessive amounts of the protein alpha-synuclein have been linked to Parkinson’s in many studies. Alpha-synuclein is a major component of Lewy bodies, the hallmark of the pathological findings in autopsies of people with PD. In addition, both rare mutations and common variants in the gene that encodes for alpha synuclein increase the risk for Parkinson’s.
To understand how normal neurons dispose excessive alpha synuclein is very important. This may help scientists understand what causes Parkinson’s (e.g., how the recycling mechanisms are faulty) and it can help scientists identify new targets for Parkinson’s treatments. Scientists can now work to find drugs that may enhance the alpha-synuclein recycling mechanisms.
Previous studies on the roles of the two recycling mechanisms, UPS and ALP in alpha-synuclein degradation have produced conflicting results. With their advanced imaging technique, Ebrahimi-Fakhari and coworkers showed that both pathways recycle alpha-synuclein: UPS is the main recycling pathway for alpha-synuclein under normal conditions, whereas ALP kicks in only when levels of alpha-synuclein are high, as in the neurons of some people with PD. Enhancing the work of UPS or making the ALS mechanism kick in sooner (before too much alpha synuclein accumulates) should be studied to slow down or even prevent Parkinson’s.
Reference: Ebrahimi-Fakhari D, Cantuti-Castelvetri I, Fan Z, Rockenstein E, Masliah E, Hyman BT, McLean PJ, Unni VK. Distinct Roles In Vivo for the Ubiquitin-Proteasome System and the Autophagy-Lysosomal Pathway in the Degradation of α-Synuclein. J Neurosci 2011 Oct.;31(41):14508–14520.
Source Date: Nov 02 2011