Parkinson's disease is associated with the spread of α-synuclein aggregates, misfolded proteins that can pass from cell to cell and encourage other α-synuclein molecules to misfold in the same way. These aggregates are surrounded by a halo of toxic biochemistry, altering cell behavior for the worse, and killing cells. The primary victims are dopaminergenic neurons necessary to motor control, leading to the characteristic symptoms of Parkinson's disease. In later stages neurons throughout the brain die, causing neurological pathologies of other sorts and eventual death.
Maintenance processes in the cell, responsible for removing damaged proteins and components, have long been an important area of research in the Parkinson's field. Mutations in genes relating to mitophagy, the process of clearing dysfunctional mitochondria, raise Parkinson's risk by making dopaminergenic neurons more vulnerable. Autophagy in general is one of the processes responsible for clearing aggregates and misfolded proteins. In today's research materials, scientists report on findings in the dysfunction of autophagy noted in Parkinson's disease, and how that might contribute to the pathological spread of α-synuclein in the brain.
Parkinson's 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, according to a new study. Parkinson's 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.
Affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. In the new study, researchers demonstrated 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 Parkinson's, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates.
Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown.
Here, we used cell-based models, including human induced pluripotent stem cell (hiPSC)-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathological pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular build-up of misfolded proteins, with consequent secretion resulting in cell-to-cell spread.
Thus, our data show that pathological protein S-nitrosylation of p62 represents a critical factor not only for autophagic inhibition and demise of individual neurons, but also for α-syn release and spread of disease throughout the nervous system.