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Scientists have identified a series of proteins that may be useful disease progression biomarkers for different types of Batten disease.

The study, “Analysis of brain and cerebrospinal fluid from mouse models of the three major forms of neuronal ceroid lipofuscinosis reveals changes in the lysosomal proteome, ”Was published in Molecular and cellular proteomics.

Neuronal lipofuscinosis (NCL) ceroids, also known as Batten disease, include a group of fatal neurodegenerative disorders in children with a wide range of symptoms, including vision loss, poor motor coordination, and impaired of cognition.

These conditions can be caused by mutations in 14 different genes (CLN1 at CLN14) that lead to the build-up of insoluble toxic waste deposits, called lipofuscins, inside cells.

New treatments, including enzyme replacement therapy and gene therapy, are now starting to be explored in clinical trials for certain types of NCL. However, biomarkers of disease progression that would be useful in assessing the effectiveness of such therapies have not yet been identified.

“To assess potential treatments for NCL, clinical evaluation systems are essential to assess long-term efficacy, but biomarkers that measure short-term response to treatment would be extremely useful,” the investigators wrote. “Such biomarkers could help optimize dose and regimen, and also provide surrogates for clinical parameters to speed up approval of effective treatments and allow rapid cessation of trials of ineffective treatments.” “

In this study, researchers at Rutgers University and their collaborators set out to search for potential disease biomarkers for the three most common types of NCL: CLN1 disease (infantile NCL), CLN2 disease (classic late infantile NCL ) and CLN3 NCL disease).

To this end, they obtained samples of brain tissue and cerebrospinal fluid (CSF, the fluid that circulates in the brain and spinal cord) from three different mouse models of NCL and compared the protein content to samples. healthy animals (controls).

Their main goal was to search for proteins whose levels were abnormally high or low compared to controls, as these would be the most likely candidates for future biomarkers of the disease.

Protein samples were collected from different stages of disease progression, and the amount of protein found on each sample was measured by a technique called isobaric labeling.

The team identified a total of 8,303 proteins in brain tissue samples and 4,905 in CSF samples. In general, most of the significant changes they found in protein levels between sick and healthy animals came from animals that were in more advanced stages of the disease.

This suggests that these changes “were a consequence of progressive neurodegeneration or other [disease] process rather than an immediate response to the metabolic defect caused by the disease gene mutation, ”the researchers wrote.

In later stages of disease progression, the researchers found a total of 445 proteins in mice with CLN1 disease and 91 in mice with CLN2 disease whose levels were significantly different from those in healthy animals.

In animals with CLN1 disease, most of these proteins were overproduced, with the exception of palmitoyl thioesterase 1 protein (PPT1, the enzyme missing in patients with CLN1 disease), whose levels were abnormally low. .

The same pattern was seen in animals with CLN2 disease, with most of the proteins found at abnormally high levels and only tripeptidyl peptidase 1 (TPP1, the enzyme lacking in patients with CLN2 disease) was in. below normal range. In mice with CLN3 disease, four proteins had abnormally high levels.

When they focused on these proteins, they found that many of them (for example TPP1, SCARB2, CD63) played a role in lysosomes – the small cell compartments that digest and recycle several molecules and whose function is impaired in NCLs – or were indicators of brain inflammation and neurodegeneration (for example NEFH, NEFL and NEFM) and could become promising NCL biomarkers.

“[S]Further studies are needed to validate the candidates identified in this study, and the use of mouse models will facilitate long-term studies to assess the response of biomarkers to disease progression, ”the researchers wrote.