The neuronal ceroid lipofuscinoses: the same, but different?

Cooper, Jonathan D.

doi:10.1042/bst0381448

Cited by 35 publications

(27 citation statements)

References 44 publications

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“…PGRN is therefore likely to be primarily implicated in lysosomal biogenesis that leads to microglial activation and microgliosis. In the present study, we showed that aged PGRNdeficient mice presented with increased accumulation of p62 and ubiquitin in the VPM/VPL, where the main pathological changes have been observed in reported NCL model mice [15][16][17][18]. p62/ubiquitin inclusions have been observed when the autophagy-lysosomal system is disrupted [26].…”

Section: Discussionmentioning

confidence: 64%

“…Neurons in the VPM/VPL project to the S1BF, and both of these structures show particular vulnerability in previously reported NCL mouse models [15]. We performed Nissl staining to compare the number of viable neurons in the VPM/VPL in 10-and 90-week-old WT and KO mice.…”

Section: Pgrn Deficiency Results In Neuronal Loss In the Vpm/vpl And mentioning

confidence: 99%

“…The NCLs display a relatively uniform phenotype in the central nervous system that is characterized by a dramatic loss of cortical neurons, pronounced gliosis, and accumulation of lysosomal autofluorescent lipopigments [14]. NCL model animals show a particular vulnerability early during disease progression in the sensory thalamocortical pathways, i.e., projections from the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL) of the thalamus to the primary somatosensory barrelfield cortex (S1BF) [15]. Localized aggregation of activated microglia and astrocytes followed by neuronal cell loss occur in this area [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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Introduction: It has been shown that progranulin (PGRN) deficiency causes age-related neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Previous studies also suggested that PGRN is involved in modulating lysosomal function. To elucidate the pathophysiological role of PGRN in the aged brain, in the present study, lysosomal function and pathological changes of the brain were investigated using 10-and 90-week-old wild-type and PGRN-deficient mice. Results: We showed that PGRN deficiency caused enhanced CD68 expression in activated microglia and astrogliosis in the cortex and thalamus, especially in the ventral posteromedial nucleus/ventral posterolateral nucleus (VPM/VPL), in the aged brain. Immunoreactivity for Lamp1 (lysosome marker) in the VPM/VPL and expression of lysosome-related genes, i.e. cathepsin D, V-type proton ATPase subunit d2, and transcription factor EB genes, were also increased by PGRN deficiency. Aggregates of p62, which is selectively degraded by the autophagy-lysosomal system, were observed in neuronal and glial cells in the VPM/VPL of aged PGRN-deficient mice. TAR DNA binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons were also observed in aged PGRN-deficient mice. PGRN deficiency caused enhanced expression of glial cell-derived cytotoxic factors such as macrophage expressed gene 1, cytochrome b-245 light chain, cytochrome b-245 heavy chain, complement C4, tumor necrosis factor-α and lipocalin 2. In addition, neuronal loss and lipofuscinosis in the VPM/VPL and disrupted myelination in the cerebral cortex were observed in aged PGRN-deficient mice.

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Section: Discussionmentioning

confidence: 64%

Section: Pgrn Deficiency Results In Neuronal Loss In the Vpm/vpl And mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice

Tanaka

Chambers

Matsuwaki

et al. 2014

Acta Neuropathologica Communications

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“…loss of SV2 was observed in the affected motor cortex but not in the spared cerebellum). Previous studies using mouse and Drosophila models of Batten disease have revealed that synaptic disruption is intimately linked to the regional onset of neurodegeneration (Cooper 2010; Bond et al. 2013), with our findings demonstrating that the relationship between synaptic pathology and neurodegeneration is likely to be similarly conserved in CLN5 sheep.…”

Section: Discussionmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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AimsSynapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease.MethodsGross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins.ResultsThe cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α‐synuclein, CSP‐α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4).ConclusionsSynaptic pathology is a robust correlate of region‐specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.

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“…One of the main consequences of this is the intralysosomal buildup of material that would otherwise have been degraded (Platt, Boland, & van der Spoel, 2012;Vitner et al, 2010;Walkley, 2007). Although opinion, and experimental evidence, varies for whether this storage material is actually harmful to cells in each LSD (e.g., Cooper, 2010;Palmer, Barry, Tyynelä, & Cooper, 2013), measuring the relative level of this storage burden in tissue sections is nevertheless very informative. Such measurements are necessarily complicated by the normal turnover of cells in somatic tissues or the loss of these cells due to the effects of disease.…”

Section: Introductionmentioning

confidence: 97%