Abstract
Synapses are an early pathological target in many neurodegenerative diseases ranging from well-known adult onset conditions such as Alzheimer and Parkinson disease to neurodegenerative conditions of childhood such as spinal muscular atrophy (SMA) and neuronal ceroid lipofuscinosis (NCLs). However, the reasons why synapses are particularly vulnerable to such a broad range of neurodegeneration inducing stimuli remains unknown. To identify molecular modulators of synaptic stability and degeneration, we have used the Cln3−/− mouse model of a juvenile form of NCL. We profiled and compared the molecular composition of anatomically-distinct, differentially-affected pre-synaptic populations from the Cln3−/− mouse brain using proteomics followed by bioinformatic analyses. Identified protein candidates were then tested using a Drosophila CLN3 model to study their ability to modify the CLN3-neurodegenerative phenotype in vivo. We identified differential perturbations in a range of molecular cascades correlating with synaptic vulnerability, including valine catabolism and rho signalling pathways. Genetic and pharmacological targeting of key ‘hub’ proteins in such pathways was sufficient to modulate phenotypic presentation in a Drosophila CLN3 model. We propose that such a workflow provides a target rich method for the identification of novel disease regulators which could be applicable to the study of other conditions where appropriate models exist.
Highlights
Synapses are an early pathological target in a range of diseases[1,2] including conditions associated with advancing age (e.g. Alzheimer (AD)[3,4] and Parkinson disease5,6), neurodevelopmental conditions (e.g. spinal muscular atrophy (SMA)7,8), protein misfolding/accumulation diseases (e.g. Huntington disease (HD)9), prion diseases[10], spinocerebellar ataxias (SCA)[11] and lysosomal storage disorders (Neuronal ceroid lipofuscinosis (NCLs or Batten disease)[12,13,14,15,16]
To investigate whether a similar pattern of synaptic pathology might be present in Cln3−/− mice we studied the expression of the presynaptic marker synaptophysin (Syp; as previously described in12) in three brain regions that exhibit different degrees of neuronal vulnerability using quantitative immunohistochemistry
We have demonstrated that such unbiased proteomic mapping of distinct pre-synaptic populations coupled with in silico analysis, and in vivo rapid phenotypic screening in Drosophila, is an effective target-rich workflow for the identification of novel molecular alterations that regulate synaptic/neuronal stability
Summary
Synapses are an early pathological target in a range of diseases[1,2] including conditions associated with advancing age (e.g. Alzheimer (AD)[3,4] and Parkinson disease5,6), neurodevelopmental conditions (e.g. spinal muscular atrophy (SMA)7,8), protein misfolding/accumulation diseases (e.g. Huntington disease (HD)9), prion diseases[10], spinocerebellar ataxias (SCA)[11] and lysosomal storage disorders (Neuronal ceroid lipofuscinosis (NCLs or Batten disease)[12,13,14,15,16]. We sought to define the molecular regulators of synaptic stability, using animal models of CLN3 disease (a.k.a. juvenile NCL or JNCL, OMIM # 204200). The knowledge of the underlying genetic cause and/or storage material composition have provided a base for the basic understandying of the pathogenesis and their correlation to the clinical progression of the disease, the design of gene replacement therapies and the development of animal models[23,24,25]. CLN3 is ubiquitously expressed throughout the body, the most obviously affected tissues are neurologic based. This feature is shared by other monogenetic neurodegenerative conditions such as SMA29. The reasons why neurons appear to be vulnerable to defects in such broadly expressed proteins is not understood
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