Lysosomal storage disorders

Lysosomal storage disorders (LSDs) highlight the diverse ways in which the failure of a single organelle can bring cells to their knees. Most are rare and poorly understood, making the development of therapies a daunting task.

Problems with the lysosome cause more than just lysosomal storage disorders. This crucial cellular component has a surprising role in several common and complex conditions.

Most rare diseases lack even one approved treatment. Regulators have tried to encourage drug development, but advocacy groups are having to fight to get the research done.

Treatments that can cross the blood–brain barrier are needed if doctors are to treat the devastating neurological symptoms of many lysosomal storage disorders.

In the 1980s, bone-marrow transplants transformed the lives of children with fatal lysosomal diseases. Researchers are now working on another revolutionary treatment.

Two competing hypotheses about Parkinson's and Gaucher's diseases need to be knitted together, say Anthony H. Futerman and John Hardy.

It is now feasible to test babies for several lysosomal storage disorders, but this goes against the gold standard for screening that was established nearly 50 years ago. The ethical issues raised are forcing a rethink of the way that newborns are screened.

The quest to understand lysosomal storage disorders (LSDs) has left researchers grappling with questions that have implications for other diseases too.

As well as degrading and recycling cellular waste, lysosomes are involved in secretion, plasma membrane repair, signalling and energy metabolism. The identification of transcription factor EB (TFEB) as a central regulator of lysosomal biogenesis and autophagy provides insight into how lysosomes adapt to environmental cues, and targeting TFEB may be a promising therapeutic strategy for modulating lysosomal function in disease.

De Leo et al. identify a lysosomal response to autophagic cargo during lysosome–autophagosome fusion that involves TLR9 activation and OCRL recruitment, and leads to a regulated local increase in PtdIns(4,5)P₂, which is necessary for a normal autophagic flux.

The concept of lysosomal storage disorders (LSDs) has existed for over 50 years, but our understanding of the causes and pathobiology of these diseases have come to light only recently, following advances in genetic technology. In this Review, Rose-Mary Boustany summarizes current understanding of known LSDs, highlighting existing treatment approaches for patients with these often devastating disorders, and outlining the barriers to development of novel therapies.

Reactive oxygen species (ROS) damage cell components, necessitating their clearance through autophagy. Here, the authors show that ROS can induce autophagy by triggering TRPML1 to release Ca²⁺from the lysosomal lumen, in turn activating the autophagy and lysosomal biogenesis regulator TFEB.

Medina, Ballabio and colleagues report that calcium release from the lysosome stimulates calcineurin, which dephosphorylates and activates TFEB. These findings reveal a central role for calcium signalling in autophagy and lysosome homeostasis.