Proteomic Analysis of Brain and Cerebrospinal Fluid from the Three Major Forms of Neuronal Ceroid Lipofuscinosis Reveals Potential Biomarkers

Clinical trials have
been conducted for the neuronal ceroid lipofuscinoses
(NCLs), a group of neurodegenerative lysosomal diseases that primarily
affect children. Whereas clinical rating systems will evaluate long-term
efficacy, biomarkers to measure short-term response to treatment would
be extremely valuable. To identify candidate biomarkers, we analyzed
autopsy brain and matching CSF samples from controls and three genetically
distinct NCLs due to deficiencies in palmitoyl protein thioesterase
1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease), and CLN3
protein (CLN3 disease). Proteomic and biochemical methods were used
to analyze lysosomal proteins, and, in general, we find that changes
in protein expression compared with control were most similar between
CLN2 disease and CLN3 disease. This is consistent with previous observations
of biochemical similarities between these diseases. We also conducted
unbiased proteomic analyses of CSF and brain using isobaric labeling/quantitative
mass spectrometry. Significant alterations in protein expression were
identified in each NCL, including reduced STXBP1 in CLN1 disease brain.
Given the confounding variable of post-mortem changes, additional
validation is required, but this study provides a useful starting
set of candidate NCL biomarkers for further evaluation.