Lysosomal storage disorders (LSDs) encompass around 70 metabolic disorders that collectively affect roughly 1 in 8000 births. They are caused by mutations in enzymes involved in lysosomal catabolism, leading to substrate accumulation and a broad range of pathologies. A significant contributor to early death in LSD patients is neurodegeneration associated with demyelination in the central nervous system (CNS). This is particularly evident in a subcategory of LSDs known as sphingolipidoses. A deeper understanding of the mechanisms of demyelination in sphingolipidoses is required to help identify effective therapies.
Randall Peterson and colleagues generated the first zebrafish model of a specific type of sphingolipidosis, known as combined saposin deficiency, by knocking out psap, which encodes four saposin glycoproteins that are important for the function of sphingolipid enzymes. The psap knockout (KO) zebrafish displayed key characteristics of combined saposin deficiency, including impaired locomotion and demyelination in the brain and optic nerve at 4 months post fertilization (mpf), as well as shortened lifespan. To interrogate the cause of demyelination, the authors characterised oligodendrocyte (OL) marker expression, as OLs are responsible for myelination in the CNS. Through quantitative real-time PCR (qRT-PCR), they found that most OL markers, apart from myelin basic protein a (mbpa), were unaltered in psap KO zebrafish compared to wild type. This suggests that demyelination was due to OL dysfunction rather than depletion. Delving into this deeper, the authors used qRT-PCR to reveal elevation of proinflammatory cytokine expression at 21 days post fertilisation, followed by increased NFκB/Jak-Stat pathway expression in the brain at 1 mpf, corresponding with declining mbpa. This implies that an inflammatory state is driving the ablation of mbpa and OL dysfunction that leads to demyelination and neuropathology at 4 mpf.
The authors then pharmacologically inhibited the NFκB pathway in juvenile and adult psap KO zebrafish, but this did not improve survival. There may, however, be alternative treatment regimens that could target these pathways more effectively. Moving on, the authors knocked out the acid sphingomyelinase, smpd1, in psap KO zebrafish, because this has shown therapeutic promise in models of other sphingolipidoses. Ablation of the acid sphingomyelinase resulted in extended survival of psap KO fish, likely due to shifting the metabolism away from the generation of toxic metabolites.
Overall, the first zebrafish model of combined saposin deficiency has shed light on mechanisms of demyelination and highlighted a potential therapeutic target. This model will be invaluable to interrogate these areas in future research.
DMM Research or Resource articles of particular interest or excellence may be accompanied by a short Editor's choice highlight, selected by a DMM editor and written by either members of the DMM in-house editorial team or an expert in the field. The Editor's choice aims to outline the challenges that the work addresses and how the work advances our insight into disease mechanism, therapy or diagnosis.
