Exploring neuroinflammatory signs in a zebrafish model of mucopolysaccharidosis type II: Early cues into pathogenic mechanisms

Mucopolysaccharidosis type II (MPS II) is a rare X-linked recessive lysosomal storage disease (LSD) caused by mutations of iduronate-2- sulfatase (IDS), a lysosomal enzyme involved in heparan and dermatan sulfate degradation. In pathological conditions, the abnormal storage of these molecules leads to a range of multisystemic symptoms affecting the central nervous system (CNS), which is extremely vulnerable to impaired lysosomal function. Indeed, LSDs neuropathological manifestations often involve microglial and astrocyte activation.In this context, I took advantage of an ids-mutant zebrafish model to describe the temporal and molecular frame of astrocyte activation. A time course-western blot analysis showed consistent Gfap (glial fibrillary acidic protein) upregulation in the midbrain of ids mutant zebrafish since 15 days post-fertilization (dpf), revealing that first signs of astrogliosis can be traced already at early developmental stages. Additionally, 15 dpf ids-mutant midbrains displayed, when compared to age matched controls, increased levels of TUNEL-positive cells paralleled by a reduction in pHH3 (Phospho-Histone H3)-positive signal thus suggesting an imbalance between cell death and proliferation. Furthermore, a preliminar investigation revealed significant dysregulation of the autophagic marker LC3-II (lipidated form of Microtubule-associated protein light chain 3) and of the Nrf2 (Nuclear factor erythroid 2-related factor 2)-mediated antioxidant response in 15 dpf ids mutant midbrains, suggesting that complex mechanisms may underlie or be triggered by astrocytes activation. Overall, my preliminary results prove that lysosomal dysfunction associates with astrocytes activation and molecular aberrations since very early stages of MPS II neuropathogenesis, supporting lysosomes central role in maintaining CNS homeostasis.