Towards a new understanding of NCL pathogenesis

Highlights

• The NCLs show certain similarities in clinical presentation and pathology.

• These broad pathological similarities mask differences between NCL subtypes.

• The timing and nature of neurodegeneration and glial activation vary markedly.

• Novel and unexpected sites of pathological changes are emerging in the brain and body.

• Should the NCLs continue to be grouped or considered as separate gene defects?

Abstract

The Neuronal Ceroid Lipofuscinoses (NCLs, Batten disease) are a group of inherited neurodegenerative disorders that have been traditionally grouped together on the basis of certain shared clinical and pathological features. However, as the number of genes that appear to cause new forms of NCL continues to grow, it is timely to reassess our understanding of the pathogenesis of these disorders and what groups them together. The various NCL subtypes do indeed share features of a build-up of autofluorescent storage material, progressive neuron loss and activation of the innate immune system. The characterisation of animal models has highlighted the selective nature of neuron loss and its intimate relationship with glial activation, rather than the generalised build-up of storage material. More recent data provide evidence for the pathway-dependent nature of pathology, the contribution of glial dysfunction, and the involvement of new brain regions previously thought to be unaffected, and it is becoming apparent that pathology extends beyond the brain. These data have important implications, not just for therapy, but also for our understanding of these disorders. However, looking beneath these broadly similar pathological themes evidence emerges for marked differences in the nature and extent of these events in different forms of NCL. Indeed, given the widely different nature of the mutated gene products it is perhaps more surprising that these disorders resemble each other as much as they do. Such data raise the question whether we should rethink the collective grouping of these gene deficiencies together, or whether it would be better to consider them as separate entities. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).