Astrocyte: Neuron Interactions in the Juvenile Form of Batten Disease

The neuronal ceroid lipofuscinosis (NCLs, Batten Disease) are inherited, fatal neurodegenerative disorders of childhood. In all forms of NCL, astrocyte activation occurs early in the disease and precedes neuronal loss. However, in the most common juvenile form (JNCL), which is caused by a mutation in the Cln3 gene, this astrocyte response appears to be compromised. Since astrocytes are crucial for the functioning and survival of neurons, and emerging evidence highlights the pivotal role that reactive astrocytosis plays in the pathogenesis of CNS diseases, any deficits in the biology of these cells could significantly impact neuronal health. In order to study the functioning of JNCL astrocytes, these cells were isolated from a well-characterised mouse model of the disease, Cln3 deficient mice (Cin3-l- mice), and their basic biology characterised. These studies revealed that Cln3-l- astrocytes have a disrupted actin and intermediate filament cytoskeleton. Possibly due to these defects, Cln3-l- astrocytes have an attenuated ability to response to an activation stimulus, just as observed in vivo, and to<br/>divide and migrate. They also display pronounced defects in their ability to take­<br/><br/>up glutamate and to secrete a range of proteins, including cytokines, neuroprotective factors and the anti-oxidant glutathione, that become even more evident upon stimulation. Additionally, their impaired calcium signalling suggests that communication might be altered in these cells. Most importantly, using a co-culture system, these Cln3-l- glia were shown to negatively impact the health of both Cln3-l- and wild-type neurons, with the mutant neurons being the most severely affected, probably because of their own compromised biology. This includes a reduction in neurite complexity and displacement of the axon initial segment (AIS), which modulates neuronal excitability and the initiation of axon potentials. Thus, these data show, for the first time, that JNCL astrocytes are functionally compromised and might play an active role in the neurodegeneration observed in JNCL. Further, this information raises the possibility that, in future, astrocytes should be considered as targets for therapeutic interventions.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2013

Author dc:creator

• Parviainen, Lotta

Advisors dc:contributor.advisor

• Williams, Brenda Patricia
• Cooper, Jonathan

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/566b0c58-a020-44ef-834c-8e7a64e6dcc5

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/566b0c58-a020-44ef-834c-8e7a64e6dcc5