Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of disorders and is collectively the most common cause of childhood onset neurodegeneration in the U.S. and worldwide. The most prevalent form of NCL onsets in the juvenile years (JNCL, or Batten disease), and is caused by recessive CLN3 mutation. JNCL children suffer from progressive blindness, seizures, phychosis, and cognitive and motor failure, and the disease is invariably fatal. CLN3 encodes a novel transmembrane protein (CLN3p, or battenin) that localizes to the endosomal-lysosomal pathway and is implicated in the regulation of ion homeostasis and vesicular trafficking, but the primary CLN3p function is yet unknown. This proposal is designed to specifically test the hypothesis that CLN3p functions to regulate vesicle acidification through the endosomal pathway, utilizing model systems that include precise genetic mouse and murine neuronal culture models that were engineered to accurately mimic the mutation most commonly associated with the human disease, and importantly, a novel, cutting-edge JNCL patient-derived, induced pluripotent stem (iPS) cell model that has recently been established by this laboratory. The approach that will be undertaken to test the specific hypothesis is: 1) To refine the location and features of the critical CLN3p function in the endocytic pathway, which is proposed to involve vesicular acidification, we will perform cell biological and biochemical assays in our murine neuronal cell culture model, including genetic and pharmacologic perturbation experiments aimed at specifically examining a putative intersection of CLN3p function and chloride channel regulation;2) To systematically identify the regulatory pathways involved in the deficiency in the endocytic pathway in JNCL, we will conduct RNAi screening and mouse genetic studies using an established high-content endocytosis assay and a mouse modeling paradigm, which have the potential to identify putative JNCL disease modifiers. These studies are also likely to identify previously unrecognized regulators of endosomal-lysosomal trafficking, and therefore could broaden our understanding of the role of endocytosis in more common neurodegenerative conditions;3) To test the hypothesis that an early consequence of CLN3p dysfunction in JNCL patient neurons is dysregulated vesicular acidification in the endocytic pathway and that mutation of other regulators of vesicular acidification can also lead to the human disease, we will perform genetic, cell biological and biochemical assays utilizing a collection of patient samples and our innovative CLN3-iPS cell model.

Public Health Relevance

Neuronal ceroid lipofuscinosis (NCL;AKA Batten disease), although classified as a rare inherited disorder, is the most common cause for neurodegeneration among children worldwide and remains poorly understood and without therapeutic treatment options. Because NCL is considered a rare disease, the pharmaceutical industry is unlikely to play a primary role in finding a cure for NCL. The study of endocytosis in NCL will also have broader impact on other more common neurodegenerative diseases that are marked by endocytic pathway involvement, including Alzheimer disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Porter, John D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code