Researchers Describe Possible Cellular Driver of Parkinson Disease Development

Recent research describes the cascade of neuronal death and the spread of abnormal protein aggregates throughout the brain in Parkinson disease.

Parkinson disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain.

The research was published in The Journal of Neuroscience.

"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," 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, said in a statement.

PD involves neuronal deaths in a characteristic sequence through key brain regions. The killing of 1 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 the later stages.

A closely related syndrome in which dementia occurs early in the disease course is called Lewy body dementia (LBD).

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 PD 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.

In this study, scientists illustrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of PD, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas, supporting the idea that this process occurs in humans.

The authors said the S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

Reference

Oh CK, Dolatabadi N, Cieplak P, et al. S-nitrosylation of p62 inhibits autophagic flux to promote α-synuclein secretion and spread in parkinson’s disease and lewy body dementia. J Neurosci. Published online February 15, 2022. doi.org/10.1523/jneurosci.1508-21.2022