Cerebrospinal Fluid Protein Biomarker Discovery in CLN3.

Syndromic CLN3-Batten is a fatal, pediatric, neurodegenerative disease caused by variants in , which encodes the endolysosomal transmembrane CLN3 protein. No approved treatment for CLN3 is currently available. The protracted and asynchronous disease presentation complicates the evaluation of potential therapies using clinical disease progression parameters.

A mouse mutant deficient in both neuronal ceroid lipofuscinosis-associated proteins CLN3 and TPP1.

Late-infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins tripeptidyl peptidase 1 (TPP1) and CLN3 protein, respectively. TPP1 is well-understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes.

Elevated levels of tripeptidyl peptidase 1 do not ameliorate pathogenesis in a mouse model of Alzheimer disease.

One potential therapeutic strategy for Alzheimer disease (AD) is to promote degradation of amyloid beta (Aβ) and we previously demonstrated that the lysosomal protease tripeptidyl peptidase 1 (TPP1) can degrade Aβ fibrils in vitro. In this study, we tested the hypothesis that increasing levels of TPP1 might promote degradation of Aβ under physiological conditions, slowing or preventing its accumulation in the brain with subsequent therapeutic benefits. We used 2 approaches to increase TPP1 activity in the brain of J20 mice, an AD model that accumulates Aβ and exhibits cognitive defects: transgenic overexpression of TPP1 in the brain and a pharmacological approach employing administration of recombinant TPP1.

A Method to Estimate the Distribution of Proteins across Multiple Compartments Using Data from Quantitative Proteomics Subcellular Fractionation Experiments.

Knowledge of cellular location is key to understanding the biological function of proteins. One commonly used large-scale method to assign cellular locations is subcellular fractionation, followed by quantitative mass spectrometry to identify proteins and estimate their relative distribution among centrifugation fractions. In most of such subcellular proteomics studies, each protein is assigned to a single cellular location by comparing its distribution to those of a set of single-compartment reference proteins.