Parviainen, L;
Dihanich, S;
Anderson, GW;
Wong, AM;
Brooks, HR;
Abeti, R;
Rezaie, P;
... Cooper, JD; + view all
(2017)
Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons.
Acta Neuropathologica Communications
, 5
, Article 74. 10.1186/s40478-017-0476-y.
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Abstract
The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in the most common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions.
| Type: | Article |
|---|---|
| Title: | Glial cells are functionally impaired in juvenile neuronal ceroid lipofuscinosis and detrimental to neurons |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s40478-017-0476-y |
| Publisher version: | http://doi.org/10.1186/s40478-017-0476-y |
| Language: | English |
| Additional information: | © The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, Juvenile batten disease, CLN3 disease, Neuronal ceroid lipofuscinosis, Neuron-glial interactions, Astrocyte and microglial dysfunction, CENTRAL-NERVOUS-SYSTEM, NECROSIS-FACTOR-ALPHA, COLONY-STIMULATING FACTORS, METHYL-D-ASPARTATE, MOUSE MODEL, BATTEN-DISEASE, NITRIC-OXIDE, IN-VITRO, THALAMOCORTICAL SYSTEM, EPILEPTIFORM ACTIVITY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10035648 |
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