Storage solutions: treating lysosomal disorders of the brain

Key Points Neurodegenerative diseases fall into two general categories: the idiopathic diseases that are associated with ageing (for example, Alzheimer's disease and Parkinson's disease) and the less common disorders that typically present in infancy or childhood, which result from monogenic defects (for example, Tay–Sachs disease). It is highly likely that unravelling the underlying pathological processes in both classes of disorder will have broad implications for the understanding and clinical management of neurodegenerative diseases as a whole. This review focuses on a family of monogenic neurodegenerative diseases, the lysosomal storage disorders. These typically result from the autosomal recessive inheritance of defects in one of the genes that encode a catabolic lysosomal enzyme. The substrate for the defective enzyme accumulates, and complex downstream pathogenic pathways are activated, leading to cellular dysfunction and, ultimately, cell death. These diseases have a high degree of clinical heterogeneity, and neuropathological symptoms include developmental delay, abnormal ocular movements, ataxia, seizures, movement disorders, spasticity, visual loss and psychiatric disease. Much recent progress has been made in understanding the pathogenic cascades that are triggered by lysosomal storage, and many storage disorders have been shown to share pathological features with the common neurodegenerative diseases — for example, atypical inflammation in the CNS, altered calcium homeostasis and altered endosomal/lysosomal function. The availability of spontaneous and engineered animal models of storage diseases has led to considerable advances in therapy, many of which are in clinical use or in clinical trials. One example of a new therapeutic approach is substrate reduction therapy (miglustat; Zavesca; Celltech/Actelion), which has been approved for use in the most common glycosphingolipid storage disease, type 1 Gaucher disease. Substrate reduction therapy is in clinical trials for neuronopathic storage diseases such as type 3 Gaucher disease, late-onset Tay–Sachs disease and Niemann–Pick disease type C. Experimental approaches such as gene therapy and neural stem cell therapy are currently being evaluated in animal disease models. The storage of molecules, either in the lysosome or at extra-lysosomal sites, is a common hallmark of many neurodegenerative conditions. The challenge now is to determine whether the failure to degrade molecules leads to a comm