The Parkinsonian Brain: Cellular Senescence and Neurodegeneration

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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.

Handwriting by a PD patient shows abnormal characteristics and micrographia. (Wikimedia)

Key clinical features of PD are impairments in motor activities including difficulty initiating voluntary movement, loss of facial expression (masked faces), and smaller handwriting (micrographia). Other non-motor symptoms include sleep disturbance, depression, and cognitive decline.

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.

In the Parkinsonian brain, dopaminergic neurons in the substantia nigra degenerate, resulting in reduced release of the dopamine neurotransmitter. (Credit: Delilah R. Cohn)

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. For example, L-DOPA is a precursor to dopamine that can be administered to patients to increase the level of dopamine synthesis. (A Nobel Prize was given to Arvid Carlsson in 2000 for showing that administration of L-DOPA reduces Parkinsonian symptoms in animal models of PD).

Other treatments include forms of pseudo-dopamine, which activate dopaminergic receptors (pramipexole, ropinirole) and drugs that inhibit dopamine breakdown (MAO inhibitors). Since the effects of these drugs are temporary, patients need to take them frequently and in increasing doses with age. So rather than replacing the lost dopamine, a better approach to treating PD would be to replace the lost dopaminergic neurons.

Our brains possess the capability to replace lost cells through a process called neurogenesis, or the formation of new neurons. Exercise and growth factors such as fibroblast growth factor 2 (FGF2) enhance neurogenesis in the brain. A logical treatment for PD would be to stimulate neurogenesis to replace lost dopaminergic 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 thathealthy 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, the Andersen and Campisi labs 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 (ie. IL-1α, IL-6, IL-8) in a phenomenon also referred to as Senescence Associated Secretory Phenotype (SASP).

Senescent astrocytes are labeled blue by uptake of beta-galactosidase. (Wikimedia)

Data from the Andersen and Campisi labs suggest 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. The Andersen and Campisi labs 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.

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Jonathon Fulkerson
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This entry was posted in Articles, Buck Institute for Research on Aging on by .

About Jonathon Fulkerson

After 15+ years as an IT professional. Jonathon decided to return to school in hopes of one day troubleshooting the most universal problem effecting all. Death, pain, and suffering by aging. As an undergraduate he is currently performing research in Dr. Richard Bennetts lab at the University of Southern Indiana, as well as volunteering for various organizations including the Buck Institute for research on Aging.

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