SATB1 is a Dopaminergic Neuron Specific Regulator of Cellular Senescence

Cellular senescence is defined as irreversible cell cycle arrest and it is characterized by the secretion of proinflammatory molecules. This cellular phenomenon is a hallmark of aging and has been lately linked to neurodegeneration in Alzheimer’s Disease [1] and paraquat induced-Parkinson Disease (PD) [2].

The work published by Riessland and colleagues [3] demonstrates for the first time how cellular senescence may play a key role in dopaminergic (DA) neuron degeneration in sporadic PD. Special AT-rich sequence-binding protein 1 (SATB1), a genetic risk factor for PD [4], regulates senescence in DA neurons in a specific manner. The authors observed that the lack of this DNA binding protein leads to senescence upregulation in both human embryonic stem cell (hESC)-derived DA neurons and mouse DA neurons, that showed a myriad of senescence hallmarks including mitochondrial alterations and upregulation of proinflammatory markers. They proposed that SATB1 controls senescence by binding to the regulatory region of CDKN1A which encodes for p21, a cyclin-dependent kinase inhibitor. These findings translate to human samples as well. A significant increase of p21 expression was found in the midbrain of sporadic PD patients, suggesting that abnormal SATB1-dependent regulation of CDKN1A could be linked to sporadic PD.

This study proposes that cellular senescence regulated by SATB1 may be a key to better understand the pathobiology of sporadic PD. These findings have major implications in the field of PD. On one hand, it points to senolytic therapy as a promising option to ameliorate the neurodegeneration observed in PD. On the other hand, it reveals SATB1 as molecular marker that operates specifically in DA neurons, which opens the door to explore whether SATB1 expression could define a particular subpopulation of DA neurons. Mouse brain in situ hybridization data show an enrichment of SATB1 in substantia nigra DA neurons [5], which suggests that cellular senescence regulated by SATB1 could be one of the mechanisms involved in the selective vulnerability of these neurons.

In conclusion, cellular senescence has been recently rediscovered in the context of neurodegeneration and its involvement in PD could change the way we understand this disease. However, caution is required since more clinical data and additional in vivo models are still needed to truly understand whether cellular senescence is a major determinant of the disease or is simply a secondary consequence of PD progression.