The Buck Institute here provides a popular science look at links between cellular senescence and the development of Parkinson's disease. The proximate cause of the symptoms of Parkinson's is the diminishing numbers and function of a small collection of dopamine generating neurons in the brain. This is a process that happens to all of us with aging, but Parkinson's patients have, for a variety of reasons, suffered more of the cell and tissue damage that leads to cell death and dysfunction in this population of neurons.
Parkinson's Disease (PD) is the second most common age-related neurological disorder in the US. Many genetic factors that contribute to an increased risk of developing PD have been identified over the years. These include mutations in the α-synuclein and Parkin genes. Additionally, epidemiology studies show increased risk of PD after exposure to pesticides and organic pollutants, as well as heavy metals. However, recent research shows that aging is a major player in the development of PD.
The motor issues present in PD patients are primarily caused by loss of dopaminergic neurons in the substantia nigra (SN) of the brain, which is a key regulator of motor movement and reward-seeking behavior. As a result, the most widely available PD treatments focus on replacing the neurotransmitter dopamine, which is produced by dopamingergic neurons, in various ways. These treatments do not halt disease progression, since dopaminergic neurons continue to degenerate even with these treatments. Instead, they only treat the symptoms of PD and make everyday life more manageable for PD patients.
Our brains possess the capability to replace lost cells through a process called neurogenesis, or the formation of new neurons. However, it turns out that the ability of the brain to produce new neurons is reduced both with age and in people who have a mutant version of α-synuclein (a major genetic risk factor for PD). This reduced capacity for neurogenesis extends to stem cell transplants in PD patients. Many groups have reported that healthy transplanted stem cells in PD patient brains show pathological characteristics over time. Thus it seems that there is something about the environment in the brain that causes healthy cells to develop the neurodegenerative characteristics of PD.
Here at the Buck Institute, we have found that cellular senescence may play a large role in the pathological neurodegeneration of PD. Cellular senescence is an anti-cancer mechanism intended to irreversibly prevent cell division when a cell is exposed to stress. Senescent cells show distinct biological markers, such as secretion of inflammatory compounds in a phenomenon also referred to as Senescence Associated Secretory Phenotype (SASP). Data suggests that cellular senescence in astrocytes may alter the brain environment to promote disease progression and inhibit neurogenesis. Astrocytes show increased levels of SASP factors, and manipulations that reduce cellular senescence also reduce Parkinsonian phenotypes in mouse models. Since cellular senescence is associated with age, astrocyte senescence may explain the age-dependency of PD onset. We are currently searching for potential treatments that can inhibit cellular senescence in the brain, thereby halting the progress of PD.
While the field of cellular senescence is relatively young in the larger field of neurobiology, it is becoming more evident that cellular senescence is key to explaining age-related disorders. Cellular senescence in the brain may prove to be one of the underlying factors common to multiple age-related neurodegenerative diseases, which would make it an important therapeutic target to pursue.