Northwestern University Feinberg School of Medicine

Kathleen Green Lab

Translational Research Targeted Toward Ameliorating Consequences of SERCA2 Loss of Function in Darier's Disease

This overview describes steps directed towards normalizing the structural and immune aspects of skin caused by impaired SERCA2 function in Darier’s disease (DD).  The outermost layer of the skin, the epidermis, is the first line of defense against the environment.  It creates an essential barrier--guarding against water loss, sunlight, pathogens and mechanical insults.  Critical for this barrier function are mechanisms that regulate the balance of extra- and intracellular calcium.   The importance of calcium in maintaining epidermal balance is underscored by Darier’s disease. This human skin disorder is caused by mutations in the gene that codes for the “sarcoplasmic endoplasmic reticulum calcium” pump, SERCA2, resulting in insufficient SERCA protein. SERCA protein is important for maintaining calcium homeostasis in cells.  Typically, one gene is affected, resulting in half the amount of SERCA2, known as “haploinsufficiency”.

Points of possible intervention in Dariers Disease.
Points of possible intervention in Dariers Disease.  (1) Directly activate the SERCA2 calcium pump to normalize calcium homeostasis and improve adhesion and reduce inflammation, (2) modulate the activity of gap junction channels to improve healing and reduce inflammation (3) modulate the unfolded protein response to improve desmosome assembly and function.

 

The insufficiency in SERCA2 resulting in altered calcium homeostasis has several major impacts:

  1. Activation of stress pathways in the cell that can impair protein structure and function;
  2. Loss of adhesion between cells of the epidermis due to improper assembly and regulation of the major epidermal adhesive junction—the desmosome; and
  3. Alterations in the immune system that lead to inflammation.  The presence of inflammatory cells and increased cytokine release by keratinocytes downstream of UV irradiation can lead to further loss of the remaining SERCA2.  The combined impact of weakened cell-cell adhesion and inflammation lead to the characteristic appearance associated with the disease. 

Treatment options for patients with Darier’s disease are limited, and an improved understanding of the molecular basis behind the adhesive dysfunction and abnormalities in calcium signaling is necessary for the development of new therapeutic targets to ameliorate this disorder. Going forward, we will consider several alternative strategies, none mutually exclusive, which could help ameliorate the impact of SERCA2 loss on skin.

Experimental Strategies