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.
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.
|Somogyi, Aleksandra; Petcherski, Anton; Beckert, Benedikt et al. (2018) Altered Expression of Ganglioside Metabolizing Enzymes Results in GM3 Ganglioside Accumulation in Cerebellar Cells of a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis. Int J Mol Sci 19:|
|Ward, Michael E; Chen, Robert; Huang, Hsin-Yi et al. (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9:|
|Huber, Robert J; Myre, Michael A; Cotman, Susan L (2017) Aberrant adhesion impacts early development in a Dictyostelium model for juvenile neuronal ceroid lipofuscinosis. Cell Adh Migr 11:399-418|
|Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222|
|Berkovic, Samuel F; Staropoli, John F; Carpenter, Stirling et al. (2016) Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease). Neurology 87:579-84|
|Chandrachud, Uma; Walker, Mathew W; Simas, Alexandra M et al. (2015) Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function. J Biol Chem 290:14361-80|
|Mole, Sara E; Cotman, Susan L (2015) Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta 1852:2237-41|
|Cotman, Susan L; Mole, Sara E; Kohan, Romina (2015) Future perspectives: Moving towards NCL treatments. Biochim Biophys Acta 1852:2336-8|
|Kohan, Romina; Mole, Sara E; Cotman, Susan L (2015) Special issue: Molecular basis of NCL. Biochim Biophys Acta 1852:2235-6|
|Huber, Robert J; Myre, Michael A; Cotman, Susan L (2014) Loss of Cln3 function in the social amoeba Dictyostelium discoideum causes pleiotropic effects that are rescued by human CLN3. PLoS One 9:e110544|
Showing the most recent 10 out of 19 publications