Synapses are an early pathological target in a wide range of neurodegenerative conditions
including adult-onset Alzheimer’s and Parkinson’s, and diseases of childhood such as spinal
muscular atrophy and neuronal ceroid lipofuscinoses (NCLs). However, our understanding of
the mechanisms regulating the stability of synapses and their exceptional vulnerability to
neurodegenerative stimuli remains in its infancy.
To address this, we have used the NCLs to model the molecular alterations underpinning
synaptic vulnerability. Our primary objective is to identify novel regulators of synaptic
stability as well as highlight novel therapeutic targets which may prove effective across multiple
neurodegenerative conditions where synapses are an early pathological target. The NCLs, are
the most frequent autosomal-recessive disease of childhood. There are currently 14 individual
genes whose mutations result in similar phenotypes including blindness, cognitive/motor
deficits, seizures and premature death. This suggests that despite the difference in the initiating
mutation and the degenerative processes across this collective group are likely to impact on
overlapping pathways.
Focusing on two murine models of NCL; one with an infantile onset - CLN1 disease (Ppt1-/-)
and one with a juvenile onset - CLN3 disease (Cln3-/-) we made use of the temporo-spatial
synaptic vulnerability pattern in these mice to plan proteomic and in silico analyses. This
pipeline was utilised to identify perturbed protein candidates and pathways correlating with
differential regional synaptic vulnerability. This ultimately allowed the generation of a list of
candidate proteins, some of which were relevant to human NCL as they were altered in post
mortem brain samples. Interestingly, many of the correlative candidates also appear to show
conserved alterations in both NCL forms examined and other neurodegenerative diseases.
Next, candidates were genetically and/or pharmacologically targeted to study their modulatory
effects on neuronal stability in vivo. This was done using CLN3 Drosophila as a rapid screening
assay and led to the successful characterisation of a subset of candidates as either enhancers or
suppressors of the CLN3-induced phenotype in vivo.
As well as identifying regulators of neuronal stability, following a similar pipeline, we
identified a set of putative biomarkers of disease progression in muscle and blood in the Ppt1-
/- mice, a subset of which appeared conserved in Cln3-/- mice. One of these conserved
candidates presented the same directionality of change in human post mortem brain samples,
indicating its relevance to the human NCL.
Following this workflow from spatio-temporal profiling of murine synaptic populations, to in
silico analyses and in vivo phenotypic assessment, we demonstrate that we can identify
multiple protein candidates capable of modulating neuronal stability in vivo and identified
putative biomarkers that tracked disease progression