Cellular Senescence in the Midbrain in the Development of Parkinson’s Disease

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Senescent cells accumulate with age throughout the body. They secrete a potent mix of signals that provoke chronic inflammation and dysfunction in cells and tissues. It is becoming increasingly clear that senescent cells are involved in brain aging, and clearance of senescent cells from the brain has been shown in animal studies to reduce chronic inflammation and pathology in the context of neurodegenerative conditions. Here, researchers argue that senescent cells are implicated in the early stages of the development of Parkinson's disease. This is a hypothesis that could be readily tested in humans, given funding for a clinical trial using the dasatinib and quercetin senolytic therapy. These therapeutics can pass the blood-brain barrier, have been assessed for their ability to clear senescent cells in the brain in animal studies, and are currently being trialed in Alzheimer's patients.

Immune responses are arising as a common feature of several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and Amyotrophic Lateral Sclerosis (ALS), but their role as either causative or consequential remains debated. It is evident that there is local inflammation in the midbrain in PD patients even before symptom onset, but the underlying mechanisms remain elusive.

In this mini-review, we discuss this midbrain inflammation in the context of PD and argue that cellular senescence may be the cause for this immune response. We postulate that to unravel the relationship between inflammation and senescence in PD, it is crucial to first understand the potential causative roles of various cell types of the midbrain and determine how the possible paracrine spreading of senescence between them may lead to observed local immune responses. We hypothesize that secretion of pro-inflammatory factors by senescent cells in the midbrain triggers neuroinflammation resulting in immune cell-mediated killing of midbrain dopaminergic neurons in PD.

Link: https://doi.org/10.3389/fnagi.2022.917797