Human iPSC-based models of neuronal ceroid lipofuscinosis capture progressive pre-storage pathology in multiple cellular compartments. J. F. Staropoli1,2,3, X. Lojewski1,4, S. Biswas1, L. Haliw1, A. Simas1, M. K. Selig2, K. A. Goss1, A. Petcherski1, S. H. Coppel1, U. Chandrachud1, S. Sheridan1, K. B. Sims5, J. F. Gusella1, D. Lucente1, D. Sondhi6, R. G. Crystal6, S. J. Haggarty1, A. Hermann4, A. Storch4, S. L. Cotman1,5 1) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA; 2) Department of Pathology, Massachusetts General Hospital, Boston, MA; 3) Division of Genetics and Genomics, Biogen Idec, Inc., Cambridge, MA; 4) Division for Neurodegenerative Diseases, Department of Neurology, Dresden University of Technology, Germany; 5) Department of Neurology, Massachusetts General Hospital, Boston, MA; 6) Department of Genetic Medicine, Weill Cornell Medical College, New York, NY.

   The neuronal ceroid lipofuscinoses (NCLs; also known as Batten disease) are a currently untreatable group of at least 13 lysosomal storage disorders that collectively comprise the most common Mendelian form of progressive neurodegeneration in childhood. The pathologic hallmark of nearly all forms of NCL is the lysosomal accumulation of subunit c of the mitochondrial ATP synthase complex in multiple cell types, including affected neurons. Little is known about the gene products underlying this presumed final common pathway, but it is clear that, as in other neurodegenerative disorders, effective intervention will require a thorough understanding of histopathologic and molecular events that well precede neuronal loss. Here we provide initial characterization of human induced pluripotent stem cell (iPSC) and iPSC-derived neuronal models of the two most common forms of NCL: classic late-infantile NCL, caused by mutations in TPP1, and juvenile NCL, caused by mutations in CLN3. These NCL genetic cell models displayed overlapping but distinct and progressive pre-storage abnormalities in multiple cellular compartments, including the endosomal-lysosomal system, particularly in multivesicular bodies, as well as in mitochondria, Golgi, and endoplasmic reticulum (ER). Differentiation of neuronal precursor cells to mature neurons recapitulated disease-specific storage material. Moreover, virally overexpressed non-mutated CLN3 rescued endosomal abnormalities in CLN3 patient cells, while virally overexpressed non-mutated TPP1 as well as treatment with the nonsense suppressor PTC124 rescued the TPP1 enzyme deficiency in TPP1-deficient neurons carrying the common nonsense mutation c.622C>T/p.Arg208X. These models represent powerful tools to assess markers and mechanisms of early NCL pathology and to screen for compounds that modify disease progression in a genotype-specific manner. JFS and XL contributed equally to this work. JFS appears first only because he is the presenting author.

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