Synaptic Function and Dysfunction in Lysosomal Storage Diseases

Abstract

Lysosomal storage diseases (LSDs) with neurological involvement are inherited genetic diseases of the metabolism characterized by lysosomal dysfunction and the accumulation of undegraded substrates altering glial and neuronal function. Often, patients with neurological manifestations present with damage to the gray and white matter and irreversible neuronal decline. The use of animal models of LSDs has greatly facilitated studying and identifying potential mechanisms of neuronal dysfunction, including alterations in availability and function of synaptic proteins, modifications of membrane structure, deficits in docking, exocytosis, recycling of synaptic vesicles, and inflammation-mediated remodeling of synapses. Although some extrapolations from findings in adult-onset conditions such as Alzheimer’s disease or Parkinson’s disease have been reported, the pathogenetic mechanisms underpinning cognitive deficits in LSDs are still largely unclear. Without being fully inclusive, the goal of this mini-review is to present a discussion on possible mechanisms leading to synaptic dysfunction in LSDs.

Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease

“…The relationship between the aberrant accumulation of proteins and lipids in the LE/Lys and synaptic dysfunction, although commonly observed in lysosomal storage disorders, is still incompletely understood at the mechanistic level. 53 CLN3 has been proposed to be present in synaptosomes 54 and recent studies in JNCL model systems support that neuronal network dysfunction and synaptic alterations may in fact precede aberrant LE/Lys storage. 55 , 56 We observed that proteins downregulated in JNCL LE/Lys compared to controls were associated with the glutamatergic and GABAergic synapse KEGG pathways.…”

Brain transplantation of genetically corrected Sanfilippo B Neural Stem Cells induces partial cross-correction of the disease

“…We found that large synaptophysin aggregates co-localized with Lamp1 staining ( Fig. 5C , white arrows), suggesting a lysosomal-mediated synaptophysin accumulation and lysosomal-mediated mechanism of synaptic failure 56 .…”

Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease

“…We found that large synaptophysin aggregates co-localized with LAMP1 staining ( Figure 5 C, white arrows) in untreated Naglu −/− mice, suggesting a lysosomal-mediated synaptophysin accumulation and mechanism of synaptic failure. 34 Alternatively these aggregates may end up in the lysosome and may fail to be broken down.

Figure 5 Correction of synaptophysin aggregation in Naglu −/− mice at 9 months (A) Representative bright-field images of 40-μm-thick half-brain coronal sections from Naglu +/− mice (Unaffected) and Naglu −/− mice injected with saline (Vehicle −/−) or N-IGFII- iNSCs (T (N-IGFII) −/−) immunohistochemically stained for synaptophysin.

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