Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Correspondence to F.M.P. e-mail: frances.platt@bioch.ox.ac.uk doi:10.1038/nrn1725 Published online 27 July 2005 Although neuronal loss is a normal event during brain development 1,2 , its inappropriate occurrence in infancy or adulthood has devastating consequences, and can result in several neurodegenerative disor- ders 3 . Progressive neuronal dysfunction and, ulti- mately, neuronal cell death define these conditions 3 , which can be subdivided into two main categories. The first comprises the relatively common diseases that are primarily associated with ageing — for example, Alzheimer’s disease and Parkinson’s disease. These disorders are typically idiopathic. Certain genetic and environmental risk factors have been proposed to increase the likelihood of developing these disorders 4 . The second group consists of the rare monogenic disorders that occur primarily in child- hood, and include the lysosomal storage disorders 5,6 . This family of diseases typically has a neurodegen- erative course. Neuropathological symptoms include developmental delay, abnormal ocular movements, ataxia, seizures, movement disorders, spasticity, visual loss and psychiatric disease (psychosis, depression and dementia). With such disparate aetiologies it might seem that these two classes of neurodegenerative disorder are unlikely to have much in common. However, it is becoming increasingly apparent that they might have several convergent pathological features, even though they are caused by different primary defects. This raises the possibility that progress towards understanding the disease process and the develop- ment of therapies in one group of disorders might have significant implications for the understanding and clinical management of the other. In this article, we focus on the lysosomal storage disorders 5,6 . The study and understanding of these diseases has been greatly facilitated by authentic animal models in several species (both spontaneous and genetically engineered) 7 and the fact that the gene and protein defect for most of these disor- ders is known and functionally understood. We review these disorders, what is known about the underlying mechanisms of their pathogenesis, and emerging strategies for therapies, some of which have progressed to clinical practice or are currently in clinical trials. As considerable progress has been made in understanding and potentially treating the diseases that are characterized by glycosphingo- lipid (GSL) storage, much of this article focuses on the glycosphingolipidoses — a subset of lysosomal disorders. STORAGE SOLUTIONS: TREATING LYSOSOMAL DISORDERS OF THE BRAIN Mylvaganam Jeyakumar, Raymond A. Dwek, Terry D. Butters and Frances M. Platt Abstract | Many neurodegenerative diseases are characterized by the accumulation of undegradable molecules in cells or at extracellular sites in the brain. One such family of diseases is the lysosomal storage disorders, which result from defects in various aspects of lysosomal function. Until recently, there was little prospect of treating storage diseases involving the CNS. However, recent progress has been made in understanding these conditions and in translating the findings into experimental therapies. We review the developments in this field and discuss the similarities in pathological features between these diseases and some more common neurodegenerative disorders. NATURE REVIEWS | NEUROSCIENCE VOLUME 6 | SEPTEMBER 2005 | 1 REVIEWS