Study shows how blocking cellular housekeeping system leads to buildup and spread of abnormal protein aggregates in the brain.
The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.
«We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain,» says study senior author Stuart Lipton, MD, PhD, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research.
Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.
In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.
One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including «housekeeping» systems that normally keep protein aggregates under control.
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Materials provided by Scripps Research Institute. Note: Content may be edited for style and length.