Characterization of Fibroblast Cells Derived from a Patient with Infantile Neuronal Ceroid Lipofuscinosis

Date of Award


Document Type

Restricted (Opt-Out)

Degree Name

Bachelor of Science



First Advisor

Quynh Chu-LaGraff




cell, human, infantile, proteins


Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a pediatric neurodegenerative disorder characterized by progressive retinal and central nervous system deterioration during infancy. This lysosomal storage disorder results from deficiency in the Palmitoyl Protein Thioesterase 1 (PPT1) enzyme; a lysosomal hydrolase which cleaves fatty acid chains such as palmitate from lipid-modified proteins. In the absence of PPT1 activity, these proteins fail to be degraded, leading to the accumulation of autofluorescent storage material in the lysosome. The underlying molecular mechanisms leading to INCL pathology remain poorly understood. A role for oxidative stress has been postulated, yet little evidence has been reported to support this possibility. Here we report the findings of a comprehensive characterization of human PPT1- deficient fibroblast cells harboring Met1Ile and Tyr247His compound heterozygous mutations. Autofluorescent storage material, characteristic of INCL, was identified in human fibroblast cells. We observed distinct organellar abnormalities of the lysosomal and mitochondrial structures, which supports previous postulations about endoplasmic reticulum and mitochondrial-mediated pathologies. There was an abundance of lysosomal compartments in the body of INCL fibroblasts, which suggests an upregulation of lysosomal biogenesis, and is known to be associated with endoplasmic reticulum stress. The mitochondrial network displayed a morphology consistent with mitochondrial dysfunction, which supports a role for the mitochondria and oxidative stress in INCL cell death. We then showed, for the first time, that human INCL fibroblasts have a heightened susceptibility to exogenous reactive oxygen species (ROS)-induced cell death, which suggests elevated basal levels of endogenous ROS in the cell. These findings offer evidence in support of a promising direction for future work investigating the molecular mechanisms underlying INCL pathology.

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