Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

Abstract

About two thirds of the patients affected with lysosomal storage diseases (LSD) experience neurological manifestations, such as developmental delay, seizures, or psychiatric problems. In order to develop efficient therapies, it is crucial to understand the neuropathophysiology underlying these symptoms. How exactly lysosomal storage affects biogenesis and function of neurons is still under investigation however recent research highlights a substantial role played by synaptic defects, such as alterations in synaptic spines, synaptic proteins, postsynaptic densities, and synaptic vesicles that might lead to functional impairments in synaptic transmission and neurodegeneration, finally culminating in massive neuronal death and manifestation of cognitive symptoms. Unveiling how the synaptic components are affected in neurological LSD will thus enable a better understanding of the complexity of disease progression as well as identify crucial targets of therapeutic relevance and optimal time windows for targeted intervention.

Keywords: Batten disease; Krabbe disease; Lysosomal storage diseases; NCL; Niemann-Pick type C; gangliosidosis; mucopolysaccharidosis; synaptic dysfunction; synaptic spines.

Figure 1

Scheme showing synaptic abnormalities (presence of axonal spheroids, demyelination, reduced synaptic vesicles, altered synaptic neurotransmission, altered spine morphology and alterations in post synaptic densities) in respective relevant LSD.