Parkinson’s disease is a progressive disease of the nervous system that affects movements. One of the telltale symptoms is tremor. It was generally thought that the disease is the result of the death of certain neurons in the brain. That results in decreased levels of dopamine, which leads to abnormal brain activity and the Parkinson’s symptoms.

Researchers with Rockefeller University discovered something completely unexpected—the affected neurons in Parkinson’s may not be dead. They found they may shut down without dying and these “undead neurons” release molecules that shut down neighboring brain cells, which leads to the common Parkinson’s symptoms. They published their research in the journal Cell Stem Cell.

These senescent cells occur throughout the body and is common when cells suffer DNA damage during division. However, senescence is not usually seen in nerve cells in the brain. Neurons halt division once fully formed. But the research group found that dopamine neurons that regulate motivation, memory and movement by producing dopamine can become senescent.

The authors state, “Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson’s, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear.”

The research focused on the function of a Parkinson’s protein called SATB1 in dopamine-producing neurons. SATB1’s activity is decreased in Parkinson’s disease. The research was led by the late Paul Greengard. Greengard’s lab partnered with researchers at Memorial Sloan Kettering to grow human stem cells into dopamine neurons in a petri dish. They then silenced the gene for SATB1.

What they found was that the neurons without SATB1 released molecules that cause inflammation and eventually senescence in neighboring neurons. The cells also showed other abnormalities, including damaged mitochondria and enlarged nuclei. None of those changes were observed in dopamine neurons with intact SATB1 or in a separate group of non-dopamine neurons without SATB1. They concluded that the senescent pathways were specific to dopamine neurons.

Analyzing the pathways involved, they discovered that SATB1 normally suppresses a gene that produces a protein called p21 that promotes senescence. SATB1 appears to protect dopamine neurons from becoming senescent. When they then reduced SATB1 in the midbrains of laboratory mice, they found the same senescence, including damaged mitochondria and high p21 levels.

In brain tissue from humans with Parkinson’s, there are also elevated p21 levels.

The research potentially explains why in Parkinson’s disease dopamine levels drop significantly before the dopamine neurons in the midbrain actually die. “They lose the function of a neuron even though they are still there,” said Markus Riessland, the lead author of the study. “People call these senescent cells zombie cells because they’re undead, basically, and because their dead-like appearance is spreading.”

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

It also opens up new therapeutic approaches. For example, there are several drugs called senolytics that remove senescent cells which may be useful in treating Parkinson’s disease. And there’s also a possibility that new drugs that target SATB1 or p21 can be developed.