CNS-Expressed Cathepsin D Prevents Lymphopenia in a Murine Model of Congenital Neuronal Ceroid Lipofuscinosis

Шевцова, З.І.; Garrido, M.; Weishaupt, Jochen H.; Säftig, Paul; Bähr, Mathias; Lühder, Fred; Kügler, Sebastian

doi:10.2353/ajpath.2010.091267

Cited by 41 publications

(32 citation statements)

References 35 publications

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“…Thus, it is likely that glial cells in the transduced area and neurons remote from AAV transduction can supply even those neurons that receive a diploid CatD gene deletion with a certain amount of CatD through extracellular secretion (Shevtsova et al, 2010). It was therefore not too surprising that no ceroid accumulation could be detected in ZFN expressing neurons.…”

Section: Resultsmentioning

confidence: 99%

Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain

Zahur

Tolö

Bähr

et al. 2017

Front. Mol. Neurosci.

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Gene editing tools like TALENs, ZFNs and Crispr/Cas now offer unprecedented opportunities for targeted genetic manipulations in virtually all species. Most of the recent research in this area has concentrated on manipulation of the genome in isolated cells, which then give rise to transgenic animals or modified stem cell lines. Much less is known about applicability of genetic scissors in terminally differentiated, non-dividing cells like neurons of the adult brain. We addressed this question by expression of a pair of ZFNs targeting the murine cathepsin D gene in CNS neurons by means of an optimized AAV viral vector. We show that ZFN expression resulted in substantial depletion of cathepsin D from neuronal lysosomes, demonstrating a robust gene deletion. Importantly, long-term ZFN expression in CNS neurons did not impair essential neuronal functionality and did not cause inflammation or neurodegeneration, suggesting that potent genetic scissors can be expressed safely in the mouse brain. This finding opens up new venues to create novel research models for neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 99%

Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain

Zahur

Tolö

Bähr

et al. 2017

Front. Mol. Neurosci.

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“…It will be interesting to investigate whether CD overexpression via adeno-associated viral (AAV) delivery may change the response to MPTP toxicity. In CD homozygous knockout mice, it was shown that exogenous CD delivered to the brain via AAV was able to prevent both neuronal and systemic pathologies associated with CD deficiency, suggesting that CD was transported from the brain to extracranial tissues in the body [18]. A mouse over expressing CD may also more effective in dealing with increases in α-synuclein levels induced by genetic over expression or MPTP treatment.…”

Section: Discussionmentioning

confidence: 99%

Dopamine and its metabolites in cathepsin D heterozygous mice before and after MPTP administration

Crabtree

Boyer-Guittaut

Ouyang

et al. 2013

Neuroscience Letters

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Cathepsin D (CD) is a lysosomal aspartyl protease which plays an important role in α-synuclein degradation, and neuronal survival. CD knockout mice die by post-natal day 25 ± 1 due to intestinal necrosis. We analyzed the young adult male heterozygous mice, and found no behavior abnormalities in the heterozygous mice compared to wildtype littermates. LC3-II, p62, and α-synuclein levels are similar, while LAMP1 is higher in the striatum in CD heterozygous compared to wildtype mice. Interestingly, we found that dopamine and metabolites in the striatum and olfactory bulbs are at higher levels than wildtype littermates, while the DOPAC/DA and HVA/DA ratio remain similar between wildtype and CD heterozygous mice. In response to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, dopamine, DOPAC, and HVA are depleted to similar levels in the striatum in both heterozygous and wildtype mice. Dopamine synthesizing enzyme tyrosine hydroxylase, metabolic enzyme monoamine oxidase, and catechol-O-methyltransferase (COMT) levels are similar in the striatum in wildtype and heterozygous mice. These studies provide valuable information regarding how lysosomal function may contribute to neurochemical homeostasis in animal models.

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“…The impact of an AAV vector-mediated expression of cathepsin D (CtsD) in either the brain or visceral organs or both on disease progression was studied in a Ctsd ko mouse [ 52 ]. Treatment of the CNS led to a widespread distribution of CtsD in neurons remote from the injection site, indicating Ctsd secretion from transduced cells and re-uptake of the enzyme by distant cells.…”

Section: Therapeutic Strategies: Preclinical Studies and Clinical Trimentioning

confidence: 99%

“…While enzyme replacement strategies that specifically target the brain have been demonstrated to effectively delay disease progression in various animal models of NCL and recently in patients with CLN2 disease (see above), they will unlikely have a significant impact on the onset and progression of retinal pathology. In fact, an AAV vector-mediated expression of CtsD in the brain of CtsD-deficient mice effectively attenuated neurodegeneration in the brain, but not in the retina [ 52 ]. Similarly, administration of TPP1 to the brain of a canine CLN2 model markedly ameliorated most neurological symptoms [ 16 , 46 ] (see also Sect.…”

Section: Treatment Strategies For Retinal Degeneration and Vision Losmentioning

confidence: 99%

Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses

et al. 2019

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The neuronal ceroid lipofuscinoses comprise a group of neurodegenerative lysosomal storage disorders caused by mutations in at least 13 different genes and primarily affect the brain and the retina of children or young adults. The disorders are characterized by progressive neurological deterioration with dementia, epilepsy, loss of vision, motor disturbances, and early death. While various therapeutic strategies are currently being explored as treatment options for these fatal disorders, there is presently only one clinically approved drug that has been shown to effectively attenuate the progression of a specific form of neuronal ceroid lipofuscinosis, CLN2 disease (cerliponase alfa, a lysosomal enzyme infused into the brain ventricles of patients with CLN2 disease). Therapeutic approaches for the treatment of other forms of neuronal ceroid lipofuscinosis include the administration of immunosuppressive agents to antagonize neuroinflammation associated with neurodegeneration, the use of various small molecules, stem cell therapy, and gene therapy. An important aspect of future work aimed at developing therapies for neuronal ceroid lipofuscinoses is the need for treatments that effectively attenuate neurodegeneration in both the brain and the retina.

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CNS-Expressed Cathepsin D Prevents Lymphopenia in a Murine Model of Congenital Neuronal Ceroid Lipofuscinosis

Abstract: Deficiency in

Cited by 41 publications

References 35 publications

Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain

Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain

Dopamine and its metabolites in cathepsin D heterozygous mice before and after MPTP administration

Current and Emerging Treatment Strategies for Neuronal Ceroid Lipofuscinoses

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