Comparative profiling of murine CLN1 Thalamus and Cortex at early and late disease timepoints



CLN1 disease or Infantile neuronal ceroid lipofuscinosis is a fatal inherited neurodegenerative lysosomal storage disease of early childhood with no currently available therapy. CLN1 disease is caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl Protein Thioesterase-1 (PPT-1). We recently found significant spinal pathology in Ppt1-deficient (Ppt1-/-) mice and human CLN1 disease, that contributes to clinical outcome, and precedes the onset of similar changes in the brain of these mice. To further understand the underlying mechanisms that cause such regional vulnerability, we used quantitative proteomic profiling to analyze the cortex and spinal cord tissue from wildtype (WT) and Ppt1-/- mice at early (3 months) and late (7 month) timepoints respectively. Tandem Mass Tagged (TMT) proteomic analysis revealed a significant early inflammatory response as well as changes in mitochondrial function, cell-signalling pathways and developmental processes in the spinal cords of Ppt1-/- mice at 3 months, as compared to their wildtype counterparts. Taken together, these early and progressive pathological and related proteomic changes in this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies for CLN1 disease. More importantly, these data fundamentally change our understanding of the progressive, site-specific disease pathogenesis in CLN1 disease, and highlight the importance of early inflammation. This will greatly impact our approach to the timing and targeting of future therapeutic trials for the neuronal ceroid lipofuscinoses (NCLs).

The proteomic data generated in the process of this research has been uploaded for general access here.

Data Citation

Wishart, Thomas. (2020). Comparative profiling of murine CLN1 Thalamus and Cortex at early and late disease timepoints, 2018-2019 [dataset]. University of Edinburgh (UK) and Washington University (St Louis, Missouri).
Date made available30 Dec 2020
PublisherEdinburgh DataShare

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