Abstract
CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, 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 brain pathology. Here, we quantified this spinal pathology at 3 and 7 months of age revealing significant and progressive glial activation and vulnerability of spinal interneurons. Tandem mass tagged proteomic analysis of the spinal cord of Ppt1−/−and control mice at these timepoints revealed a significant neuroimmune response and changes in mitochondrial function, cell-signalling pathways and developmental processes. Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many similarly affected processes, except the inflammatory response. These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data also fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. This should greatly impact our approach to the timing and targeting of future therapeutic trials for this and similar disorders.
Highlights
CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1)
Stereological estimates of Nisslstained sections of 3 and 7 month old wildtype and Ppt1−/− mouse spinal cords[10,11] revealed significantly lower total volume, grey matter and white matter volumes at 3 months of age in Ppt1−/− mice, which worsened by 7 months of age (Fig. 1A)
The similar effects within dorsal and ventral horns suggest that these glial changes are not confined to either sensory or motor pathways, unlike the regional specificity observed in the brain and cerebellum[12,13]
Summary
CLN1 disease is a fatal inherited neurodegenerative lysosomal storage disease of early childhood, caused by mutations in the CLN1 gene, which encodes the enzyme Palmitoyl protein thioesterase-1 (PPT-1). Comparing proteomic changes in the spinal cord and cortex at 3 months revealed many affected processes, except the inflammatory response These proteomic and pathological data from this largely unexplored region of the CNS may help explain the limited success of previous brain-directed therapies. These data fundamentally change our understanding of the progressive, site-specific nature of CLN1 disease pathogenesis, and highlight the importance of the neuroimmune response. Dysfunction and most notably, a significant neuroinflammatory response in the spinal cords of Ppt1−/− mice at 3 months of age that is not observed in their cortex at the same age Together, these data highlight the significant and early extent of disease in the CLN1 disease spinal cord, identifying vulnerable spinal cell populations and region-specific disease mechanisms that may underlie spinal cord vulnerability in this disease
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