Abstract
Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases.
Highlights
Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases and constitute the most common group of pediatric neurodegenerative disorders
The initial CLN5Y392X induced pluripotent stem cells (iPSCs) colony selection was based on morphologic resemblance to human embryonic stem cell (ESC) colonies (Figure 1B)
In this study we describe the generation and characterisation of human induced pluripotent stem cells derived from a CLN5 patient, suffering from a variant form of pediatric neurodegenerative NCL
Summary
Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases and constitute the most common group of pediatric neurodegenerative disorders. NCLs are caused by mutations in at least 14 different genes (CLN1–CLN14) and share several clinical and pathological features including visual impairment, seizures, brain atrophy and storage of lysosomal autofluorescent ceroid, lipofuscin-like material [1,2,3,4]. We focus on CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, a late infantile variant NCL (MIM#256731), caused by mutations in the CLN5 gene [5,6,7]. In the late infantile variant form of the CLN5 disease, the first symptoms, motor clumsiness and attention disturbances, appear between 4–7 years of age and are followed by progressive visual failure, motor and mental decline, ataxia, myoclonia and epilepsy, and an early death between the second and fourth decades of life [7,10]. The CLN5 patients’ brains show the earliest and most severe atrophy in the cerebellum accompanied by storage deposition, destruction of cerebral neurons, astrocytosis and hypomyelination [11,12,13]
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