Roles of CLN7 in neurodevelopment

Mohammed, Alamin ORCID: 0000-0001-9580-6119 (2020). Roles of CLN7 in neurodevelopment. University of Birmingham. Ph.D.

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Abstract

The neuronal ceroid lipofuscinoses (NCLs) are group of neurodegenerative disorders with infantile or childhood onset. The NCLs result in a progressive decline in cognitive and motor functions, seizures and loss of vision that is clinically characterised by the build-up of autofluorescent storage material in lysosomes. Mutations in CLN7 lead to a late-infantile form of NCL. CLN7 encodes a putative lysosomal transmembrane transport protein, but its substrate remains unknown and the biology underpinning the disease is not understood. In this thesis, I used CRISPR/Cas9 genome editing in Drosophila to generate a YFP-CLN7 knock-in to enable the first in vivo localisation study of CLN7 without overexpression. Within the CNS, CLN7 was predominately expressed in glial cells that form the insect blood-brain-barrier, with neuronal expression being restricted to visual neurons. CLN7 was also found to localise to the postsynaptic site of the larval neuromuscular junction (NMJ). CLN7-deficient larvae showed significant reductions in synapse size with genetic studies using GAL4/UAS revealing post-synaptic expression of CLN7 in muscles being crucial for NMJ development. Autophagy and the retrograde TGF-β pathways that regulate NMJ development were unaffected by the loss of CLN7. Autofluorescent material was observed in the visual system of aged CLN7 flies, recapitulating a key hallmark of the human disease. I also identified functional defects in vision. Taken together, dysregulation of synapses at the NMJ and the visual system indicate a fundamental role for CLN7 in neurodevelopment.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):