Targeting Dopaminergic Neurons in ‘Zombie’ State Might Slow Parkinson’s Progression, Study Says

Targeting Dopaminergic Neurons in ‘Zombie’ State Might Slow Parkinson’s Progression, Study Says

Contrary to what is commonly thought, dopamine-producing nerve cells (neurons) that stop functioning in Parkinson’s disease may not die, but instead enter a state of senescence in which they cease to divide and cause damage to healthy neighboring cells, a study found.

In fact, one researcher noted these senescence cells are considered “zombie cells,” a spreading “undead.”  Future therapies that specifically stop senescence may help prevent the disease or slow its progression.

The study, “Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons,” was published in the journal Cell Stem Cell.

A key hallmark of Parkinson’s disease (PD) is the progressive degeneration of dopaminergic neurons in the brain, resulting in its characteristic motor symptoms.

During the natural process of aging, the main risk factor for both the sporadic and genetic forms of PD, humans and other organisms accumulate senescent cells within their tissues. Cellular senescence refers to when cells cease to divide and grow, and can no longer regenerate tissues.

While cellular senescence is important in both embryonic development and wound healing, and plays a role in preventing the development of certain cancers (by arresting uncontrolled cell growth), it can become detrimental.

Senescent cells tend to emit chemicals into their environment that can damage surrounding cells. In addition to accumulating in healthy, older tissue, senescent cells can abnormally accumulate in disease states.

In fact, recent studies have reported increased markers of cellular senescence in the brains of Parkinson’s patients.

Special AT-rich sequence-binding protein 1 (SATB1) was recently identified as a risk factor for PD. Previous studies have shown that SATB1’s activity is reduced in the most affected brain regions of patients.

Researchers set out to investigate SATB1’s role in dopamine-producing neurons, whose activity is lower than usual in Parkinson’s disease.

The team differentiated human stem cells into dopaminergic neurons in a lab dish; in some of these neurons, they silenced the gene responsible for producing the SATB1 protein.

Genetic deletion of SATB1 induced senescence in dopaminergic nerve cells. In particular, researchers found that a lack of SATB1 led to the characteristic hallmarks of cellular senescence, such as increased oxidative protein damage, damaged mitochondria — a cell’s “powerhouse” or energy source — and enlarged nuclei.

Dopaminergic neurons lacking SATB1 also released certain molecules that caused inflammation and senescence in surrounding neurons.

Further analysis found that in healthy dopaminergic neurons, SATB1 directly binds to the regulatory region of the p21 gene and represses its expression. This gene produces a protein known to promote senescence. As such, in a healthy scenario, SATB1 prevents dopaminergic neurons from entering senescence.

Eliminating SATB1 from another type of neuron, called CTX neurons, did not induce senescence or affected p21 expression.

The researchers believe that “SATB1-dependent repression of [p21] transcription seems to be crucial for [dopaminergic] neuron function.”

These findings may explain why Parkinson’s patients experience a drop in dopamine levels before dopamine neurons actually die.

“They [dopaminergic neurons] loose the function of a neuron even though they are still there,” Markus Riessland, the study’s lead author, said in a press release. “People call these senescent cells zombie cells because they’re undead, basically, and because their dead-like appearance is spreading.”

Reducing the activity of SATB1 in dopaminergic neurons in mice also resulted in the same signs of senescence and high levels of p21 and a local immune reponse.

These senescent neurons “stop the cell cycle and they start secreting inflammatory factors that signal to the immune system, ‘Come here and eat me,’” Riessland explained. “This might really be a novel explanation for why you see certain markers of inflammation in Parkinson’s Disease.”

Importantly, researchers found that p21 is actively expressed in dopaminergic neurons of Parkinson’s patients with the sporadic form of the disease, making these cells more prone to enter into a state of senescence.

The team believes that SATB1 could be a promising target for novel therapies that target senescent cells, called senolytics, which have already been able to improve age-related manifestations in mice.

Importantly, therapeutic strategies that target SATB1 or p21 in Parkinson’s disease could be a “beneficial route to intervention.”

Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors.
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Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.
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Iqra holds a MSc in Cellular and Molecular Medicine from the University of Ottawa in Ottawa, Canada. She also holds a BSc in Life Sciences from Queen’s University in Kingston, Canada. Currently, she is completing a PhD in Laboratory Medicine and Pathobiology from the University of Toronto in Toronto, Canada. Her research has ranged from across various disease areas including Alzheimer’s disease, myelodysplastic syndrome, bleeding disorders and rare pediatric brain tumors.
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