LYSOCIL CEDOC-NMS I FCM special seminar with Professor Hans Aerts

June 23, 2021 @Zoom

A special LYSOCIL CEDOC-NMS I FCM seminar was held on 23rd June 2021 with Professor Hans Aerts  from the Department of Medical Biochemistry, Leiden University, The Netherlands. This seminar was dedicated to “Gaucher disease; new developments regarding a prototypic lysosomal storage disorder”.

Abstract: Gaucher disease (GD), a more common inherited lysosomal storage disorder (LSD) has acted as a frontrunner in many areas, as will be discussed. The molecular basis of GD was elucidated among the first of the LSDs, being an inherited deficiency in lysosomal beta-glucosidase activity as the result of mutations in the GBA gene.  The beta-glucosidase involved in GD is usually designated as glucocerebrosidase (GCase; GBA1). Its primary substrate is a simple glycosphingolipid, glucosylceramide. Already some 40 years ago an effective treatment of GD patients without CNS involvement was developed based on chronic administration of the deficient GCase enzyme, so-called enzyme replacement therapy. This ERT approach was subsequently copied for other LSDs. An alternative treatment based on substrate reduction was also firstly developed for GD. Already in 2001 the first compound was registered as drug for substrate reduction therapy (SRT) of mild to moderate GD. Meanwhile improved SRT agents are in development and some are already registered and applied. Other therapy avenues for GD are intensely investigated such as chaperone and gene therapies. The lecture will also touch upon  laboratory research in which GD acted again as a frontrunner. Discussed will be the nowadays widely applied plasma biomarkers for pathological storage cells (so-called Gaucher cells, lipid-laden macrophages). Special attention will be paid to the occurrence of massively elevated glucosylsphingosine in plasma and tissues of GD patients, a finding again exploited for diagnosis and disease monitoring. We were able to demonstrate that water-soluble glucosylsphingosine is actively generated from accumulating primary storage lipid glucosylceramide by deacylation. The same phenomenon occurs also in other LSDs in which sphingolipids accumulate, resulting in massively elevated corresponding deacylated lipids. The potential toxicity and contribution of these deacylated lipids to symptoms in sphingolipid LSDs will be discussed. Finally attention is paid to very recently discovered unknown catalytic activities of GCase and connected to this newly discovered glycolipids.

Rare Disease