Neuronal ceroid lipofuscinosis/Batten disease: the lysosomal proteinoses

Gupta, Praveena; Hofmann, Sandra L.

doi:10.1038/sj.mp.4001127

Cited by 4 publications

(2 citation statements)

References 8 publications

(6 reference statements)

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“…The neuropathologic defects of CtsD-KO mice manifest a phenotype that resembles NCLs 5 – 7 . In the brain of CtsD-KO mice, the accumulated storage material appears in membrane-delimited organelles with the structure and staining characteristics of ‘residual bodies’, the presumed end result of lysosomal degradation in the cell 8 , 9 . The storage material contains subunit c of mitochondrial ATP synthase, indicating that the autophagy-lysosome system is impaired 5 .…”

Section: Introductionmentioning

confidence: 99%

Lack of Cathepsin D in the central nervous system results in microglia and astrocyte activation and the accumulation of proteinopathy-related proteins

Suzuki

Yamaguchi

Sanada

et al. 2022

Sci Rep

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Neuronal ceroid lipofuscinosis is one of many neurodegenerative storage diseases characterized by excessive accumulation of lipofuscins. CLN10 disease, an early infantile neuronal ceroid lipofuscinosis, is associated with a gene that encodes cathepsin D (CtsD), one of the major lysosomal proteases. Whole body CtsD-knockout mice show neurodegenerative phenotypes with the accumulation of lipofuscins in the brain and also show defects in other tissues including intestinal necrosis. To clarify the precise role of CtsD in the central nervous system (CNS), we generated a CNS-specific CtsD-knockout mouse (CtsD-CKO). CtsD-CKO mice were born normally but developed seizures and their growth stunted at around postnatal day 23 ± 1. CtsD-CKO did not exhibit apparent intestinal symptoms as those observed in whole body knockout. Histologically, autofluorescent materials were detected in several areas of the CtsD-CKO mouse’s brain, including: thalamus, cerebral cortex, hippocampus, and cerebellum. Expression of ubiquitin and autophagy-associated proteins was also increased, suggesting that the autophagy-lysosome system was impaired. Microglia and astrocytes were activated in the CtsD-CKO thalamus, and inducible nitric oxide synthase (iNOS), an inflammation marker, was increased in the microglia. Interestingly, deposits of proteinopathy-related proteins, phosphorylated α-synuclein, and Tau protein were also increased in the thalamus of CtsD-CKO infant mice. Considering these results, we propose thatt the CtsD-CKO mouse is a useful mouse model to investigate the contribution of cathepsin D to the early phases of neurodegenerative diseases in relation to lipofuscins, proteinopathy-related proteins and activation of microglia and astrocytes.

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Section: Introductionmentioning

confidence: 99%

Lack of Cathepsin D in the central nervous system results in microglia and astrocyte activation and the accumulation of proteinopathy-related proteins

Suzuki

Yamaguchi

Sanada

et al. 2022

Sci Rep

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“…The neuropathologic defects of CtsD-KO mice manifest a phenotype that resembles NCLs [5][6][7] . In the brain of CtsD-KO mice, the accumulated storage material appears in membrane-delimited organelles with the structure and staining characteristics of 'residual bodies', the presumed end result of lysosomal degradation in the cell 8,9 . The storage material contains subunit c of mitochondrial ATP synthase, indicating that the autophagy-lysosome system is impaired 5 .…”

Section: Introductionmentioning

confidence: 99%

Lack of Cathepsin D in the Central Nervous System Results in Microglia and Astrocyte Activation and the Accumulation of Proteinopathy-related Proteins

Suzuki

Yamaguchi

Sanada

et al. 2021

Preprint

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Neuronal ceroid lipofuscinosis is one of many neurodegenerative storage diseases characterized by excessive accumulation of lipofuscins. CLN10 disease, an early infantile neuronal ceroid lipofuscinosis, is associated with a gene that encodes cathepsin D (CtsD), one of the major lysosomal proteases. Whole body CtsD-knockout mice show neurodegenerative phenotypes with the accumulation of lipofuscins in the brain and also show defects in other tissues including intestinal necrosis. To clarify the precise role of CtsD in the central nervous system (CNS), we generated a CNS-specific CtsD-knockout mouse (CtsD-CKO). CtsD-CKO mice were born normally but developed seizures and their growth stunted at around postnatal day 23±1. CtsD-CKO did not exhibit apparent intestinal symptoms as those observed in whole body knockout. Histologically, autofluorescent materials were detected in several areas of the CtsD-CKO mouse’s brain, including: thalamus, cerebral cortex, hippocampus, and cerebellum. Expression of ubiquitin and autophagy-associated proteins was also increased, suggesting that the autophagy-lysosome system was impaired. Microglia and astrocytes were activated in the CtsD-CKO thalamus, and Inducible nitric oxide synthase (iNOS), an inflammation marker, was increased in the microglia. Interestingly, deposits of proteinopathy-related proteins, phosphorylated α-synuclein and Tau protein, were also increased in the thalamus of CtsD-CKO infant mice. Considering these results, it is likely that the CtsD-CKO mouse is a useful mouse model to investigate the contribution of cathepsin D to the early phases of neurodegenerative diseases in relation to lipofuscins, proteinopathy-related proteins and activation of microglia and astrocytes.

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Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis

Cooper

2003

Current Opinion in Neurology

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Neuronal ceroid lipofuscinosis/Batten disease: the lysosomal proteinoses

Cited by 4 publications

References 8 publications

Lack of Cathepsin D in the central nervous system results in microglia and astrocyte activation and the accumulation of proteinopathy-related proteins

Lack of Cathepsin D in the central nervous system results in microglia and astrocyte activation and the accumulation of proteinopathy-related proteins

Lack of Cathepsin D in the Central Nervous System Results in Microglia and Astrocyte Activation and the Accumulation of Proteinopathy-related Proteins

Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis

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