Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses

Abstract

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional “neuron-centric” view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research.

TUNEL‐positive structures in activated microglia and SQSTM1/p62‐positive structures in activated astrocytes in the neurodegenerative brain of a CLN10 mouse model

“…Electron microscopy revealed that granular osmiophilic deposits (GROD, abnormal lysosomal structures) and abnormal autophagic structures accumulated in the neurons of CtsD flox/flox ; Nestin‐Cre mice (Suzuki et al, 2022). Furthermore, activated astrocytes and microglia are increased in the brains of CtsD flox/flox ; Nestin‐Cre mice, as is the case in other NCL mouse models (Takahashi et al, 2022). However, the morphological association of SQSTM1/p62‐positive signals and GRODs in activated glial cells of CtsD flox/flox ; Nestin‐Cre mice has not been studied because of the difficulty in identifying the complicated ultrastructure of activated microglia and astrocytes in the brain (Savage et al, 2018).…”

“…Electron microscopy revealed that granular osmiophilic deposits (GROD, abnormal lysosomal structures) and abnormal autophagic structures accumulated in the neurons of CtsD flox/flox ; Nestin-Cre mice (Suzuki et al, 2022). Furthermore, activated astrocytes and microglia are increased in the brains of CtsD flox/flox ; Nestin-Cre mice, as is the case in other NCL mouse models (Takahashi et al, 2022).…”

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

“…Localized glial activation of both astrocytes and microglia is another pathological hallmark of NCLs, including CLN2 disease (37). To assess whether interneuron-specific TPP1 deficiency triggers glial activation, we performed immunohistochemistry on brain sections of 15-week-old Vgat-Cre; TPP1LAMP1 mice for glial fibrillary acidic protein (GFAP), a marker for astrogliosis, and CD68, a marker for microglial activation (37, 38). Immunohistological analysis revealed a marked increase in both GFAP and CD68 immunoreactivities in age-matched Cln2 R207X/R207X mice across CPu, S1BF, and VPM/VPL, but no significant increase was observed within any of these brain regions of Vgat-Cre; TPP1LAMP1 mice compared to age-matched TPP1LAMP1 mice (Figure 3A and B).…”

Sortilin inhibition treats multiple neurodegenerative lysosomal storage disorders

“…53 We examined hallmark neuroinflammation in brain regions known to be involved in Batten pathogenesis, namely the ventral posterolateral and ventral posteromedial nuclei (VPM/VPL) of the thalamus, the somatosensory cortex barrel field (S1BF), the CA3 region of the hippocampus, and the dentate gyrus (DG) and hilus regions of the hippocampus. [74][75][76] In Cln2 R207X mice, treatment with AF38469 (0.3 μg/ml) slightly reduced levels of mitochondrial ATP synthase subunit C (SubC), a primary constituent of the lysosomal storage material, in the S1BF of the somatosensory cortex, CA3 of the hippocampus, and VPM/VPL of the thalamus (Figure 3D-F). 77 Cln2 R207X mice treated with AF38469 had reduced levels of microglial reactivity (CD68 + ) in the VPM/VPL of the thalamus while no impact was observed in other regions (Figure 3F).…”