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Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases

Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain...

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Autores principales: Sambri, Irene, D'Alessio, Rosa, Ezhova, Yulia, Giuliano, Teresa, Sorrentino, Nicolina Cristina, Cacace, Vincenzo, De Risi, Maria, Cataldi, Mauro, Annunziato, Lucio, De Leonibus, Elvira, Fraldi, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210158/
https://www.ncbi.nlm.nih.gov/pubmed/27881461
http://dx.doi.org/10.15252/emmm.201606965
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author Sambri, Irene
D'Alessio, Rosa
Ezhova, Yulia
Giuliano, Teresa
Sorrentino, Nicolina Cristina
Cacace, Vincenzo
De Risi, Maria
Cataldi, Mauro
Annunziato, Lucio
De Leonibus, Elvira
Fraldi, Alessandro
author_facet Sambri, Irene
D'Alessio, Rosa
Ezhova, Yulia
Giuliano, Teresa
Sorrentino, Nicolina Cristina
Cacace, Vincenzo
De Risi, Maria
Cataldi, Mauro
Annunziato, Lucio
De Leonibus, Elvira
Fraldi, Alessandro
author_sort Sambri, Irene
collection PubMed
description Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α‐synuclein and increased proteasomal degradation of cysteine string protein α (CSPα). As a result, the availability of both α‐synuclein and CSPα at nerve terminals strongly decreases, thus inhibiting soluble NSF attachment receptor (SNARE) complex assembly and synaptic vesicle recycling. Aberrant presynaptic SNARE phenotype is recapitulated in mice with genetic ablation of one allele of both CSPα and α‐synuclein. The overexpression of CSPα in the brain of a mouse model of mucopolysaccharidosis type IIIA, a severe form of LSD, efficiently re‐established SNARE complex assembly, thereby ameliorating presynaptic function, attenuating neurodegenerative signs, and prolonging survival. Our data show that neurodegenerative processes associated with lysosomal dysfunction may be presynaptically initiated by a concomitant reduction in α‐synuclein and CSPα levels at nerve terminals. They also demonstrate that neurodegeneration in LSDs can be slowed down by re‐establishing presynaptic functions, thus identifying synapse maintenance as a novel potentially druggable target for brain treatment in LSDs.
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spelling pubmed-52101582017-01-05 Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases Sambri, Irene D'Alessio, Rosa Ezhova, Yulia Giuliano, Teresa Sorrentino, Nicolina Cristina Cacace, Vincenzo De Risi, Maria Cataldi, Mauro Annunziato, Lucio De Leonibus, Elvira Fraldi, Alessandro EMBO Mol Med Research Articles Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α‐synuclein and increased proteasomal degradation of cysteine string protein α (CSPα). As a result, the availability of both α‐synuclein and CSPα at nerve terminals strongly decreases, thus inhibiting soluble NSF attachment receptor (SNARE) complex assembly and synaptic vesicle recycling. Aberrant presynaptic SNARE phenotype is recapitulated in mice with genetic ablation of one allele of both CSPα and α‐synuclein. The overexpression of CSPα in the brain of a mouse model of mucopolysaccharidosis type IIIA, a severe form of LSD, efficiently re‐established SNARE complex assembly, thereby ameliorating presynaptic function, attenuating neurodegenerative signs, and prolonging survival. Our data show that neurodegenerative processes associated with lysosomal dysfunction may be presynaptically initiated by a concomitant reduction in α‐synuclein and CSPα levels at nerve terminals. They also demonstrate that neurodegeneration in LSDs can be slowed down by re‐establishing presynaptic functions, thus identifying synapse maintenance as a novel potentially druggable target for brain treatment in LSDs. John Wiley and Sons Inc. 2016-11-23 2017-01 /pmc/articles/PMC5210158/ /pubmed/27881461 http://dx.doi.org/10.15252/emmm.201606965 Text en © 2016 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Sambri, Irene
D'Alessio, Rosa
Ezhova, Yulia
Giuliano, Teresa
Sorrentino, Nicolina Cristina
Cacace, Vincenzo
De Risi, Maria
Cataldi, Mauro
Annunziato, Lucio
De Leonibus, Elvira
Fraldi, Alessandro
Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
title Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
title_full Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
title_fullStr Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
title_full_unstemmed Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
title_short Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
title_sort lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210158/
https://www.ncbi.nlm.nih.gov/pubmed/27881461
http://dx.doi.org/10.15252/emmm.201606965
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