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Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 https://dx.doi.org/10.20517/rdodj.2023.37 Page 3 of 11

[12]
Fabry patients .

Inflammatory pathway activation is also manifested by the presence of complement-activated components
[13]
C3 and iC3b in the GLA knockout mouse model and in the serum, plasma, and brain of patients with
[14]
Fabry disease .

Target organs in Fabry disease, the nervous system, kidney, and heart, suffer from infiltration with immune
cells that are recruited through an attempt to mitigate and heal the harmful effects of lysosomal deposits.
Nervous system affection is marked by the recruitment of immune cells, as observed in the autonomic and
peripheral nervous system associated with activating microglia, NK cells, macrophages, and dendritic cells
in central and peripheral tissues . Immune infiltration of T cells and macrophages is also observed in
[15]
cardiac and renal tissues [6,16] .

Tubular cells collected from urine samples of Fabry patients revealed impairment of mitochondrial
morphology and increased oxygen consumption rate, reflecting mitochondrial dysfunction . These
[17]
[18]
alterations increase autophagy, producing ROS production and proapoptotic signaling . These data
suggest that mitochondrial dysfunction can contribute to inflammation pathways and renal damage.

Overall, experimental models and human investigation data are consistent with Fabry disease. The
interaction between Gb3 and immunocompetent cells causes a subtle, chronic, insidious activation of innate
immunity and associated processes, resulting in an overlooked inflammation. Acute inflammation is a
physiological response to eliminate damage in cells or tissues. However, if the damage can not be
eliminated, as in Fabry disease, inflammation becomes chronically stimulated due to continuously
producing glycolipid deposits. Chronic inflammation induces a scar formation that replaces normal
parenchyma with fibrotic tissue, leading to loss of organ function .
[19]

GLA GENE AND ENDOPLASMIC RETICULUM STRESS: THE ROLE OF UNFOLDED
PROTEIN RESPONSE
In the survey to elucidate the pathophysiology of organ affection in Fabry disease patients, the pathogenic
role of endoplasmic reticulum [ER] stress and unfolded protein response [UPR] emerged as a possible
hypothesis. The endoplasmic reticulum physiologically checks the correct folding of proteins before
releasing them and amends or stops those with altered structures. Many Fabry disease pathogenic variants
are missense, and mutated proteins are misfolded and retained in the ER instead of transported to the
lysosome . High ER retention of misfolded proteins leads to ER stress, and if this stress is maintained, it
[20]
leads to the activation of UPR. The UPR is a sophisticated collection of intracellular signaling pathways that
have evolved to respond to protein misfolding in the ER. In addition, it has become increasingly clear that
UPR signaling is essential in immunity and inflammation . There is a reciprocal regulation between ER
[21]
stress and inflammation whereby ER stress can activate inflammatory pathways, and, in turn, pro-
inflammatory stimuli can trigger ER stress, such that the resulting UPR activation can further amplify
[22]
inflammatory responses . UPR activation in immune cells and various stromal cells leads to the induction
and secretion of cytokines, such as IL-6 and TNF. Conversely, cytokines themselves can directly regulate the
UPR .
[23]
Apoptotic cell death mediated by UPR is carried out by the initiator caspase 12 and caspase 4. A study on
mononuclear cells from Fabry patients revealed higher levels of caspase 12 but variable results of caspase 4.
Further investigation showed no differences in ER stress-associated genes’ expression levels, ruling out ER
stress’s involvement in mononuclear cells from Fabry patients’ apoptotic cell death .
[11]