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Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

BACKGROUND: The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency) impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC...

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Autores principales: Lopez, Manuel E, Klein, Andres D, Scott, Matthew P
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511250/
https://www.ncbi.nlm.nih.gov/pubmed/22985423
http://dx.doi.org/10.1186/1742-2094-9-216
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author Lopez, Manuel E
Klein, Andres D
Scott, Matthew P
author_facet Lopez, Manuel E
Klein, Andres D
Scott, Matthew P
author_sort Lopez, Manuel E
collection PubMed
description BACKGROUND: The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency) impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC), caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1(-/-) mice. Here we test whether complement is mediating neurodegeneration in NPC disease. FINDINGS: In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs). In Npc1(-/-) mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG). Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. CONCLUSION: We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders.
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spelling pubmed-35112502012-12-01 Complement is dispensable for neurodegeneration in Niemann-Pick disease type C Lopez, Manuel E Klein, Andres D Scott, Matthew P J Neuroinflammation Short Report BACKGROUND: The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency) impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC), caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1(-/-) mice. Here we test whether complement is mediating neurodegeneration in NPC disease. FINDINGS: In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs). In Npc1(-/-) mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG). Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. CONCLUSION: We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders. BioMed Central 2012-09-17 /pmc/articles/PMC3511250/ /pubmed/22985423 http://dx.doi.org/10.1186/1742-2094-9-216 Text en Copyright ©2012 Lopez et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Report
Lopez, Manuel E
Klein, Andres D
Scott, Matthew P
Complement is dispensable for neurodegeneration in Niemann-Pick disease type C
title Complement is dispensable for neurodegeneration in Niemann-Pick disease type C
title_full Complement is dispensable for neurodegeneration in Niemann-Pick disease type C
title_fullStr Complement is dispensable for neurodegeneration in Niemann-Pick disease type C
title_full_unstemmed Complement is dispensable for neurodegeneration in Niemann-Pick disease type C
title_short Complement is dispensable for neurodegeneration in Niemann-Pick disease type C
title_sort complement is dispensable for neurodegeneration in niemann-pick disease type c
topic Short Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511250/
https://www.ncbi.nlm.nih.gov/pubmed/22985423
http://dx.doi.org/10.1186/1742-2094-9-216
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