Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

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.

Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

“…; Uusi‐Rauva et al . ). Retinal degeneration and visual impairment are the first signs of juvenile neuronal ceroid lipofuscinosis caused by ceroid lipofuscinosis, neuronal 3, juvenile (Batten, Spielmeyer‐Vogt disease) (CLN3) mutations, followed by inevitable progression to blindness (Hall et al .…”

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

“…Tangier disease (mutations in ABCA1 ), lysosomal storage diseases including neuronal ceroid lipofuscinoses (NCLs) 27 and Gaucher disease (GD, mutations in GBA ), 28, 29 chronic granulomatous disease (CGD, defective NADPH oxidase), 30 Blau syndrome (mutation in NOD2 ), 31 and chronic infantile neurologic cutaneous and articular syndrome (CINCA syndrome, mutation in NLRP3 ). 32 Some of these studies compared the phenotypes of IPSDM and HMDM derived from the same subjects 8, 29 to further validate the fidelity of IPSDM in assessing the functionality of genetic mutations.…”

Small Molecules that Rescue Multiple Phenotypic Aberrations in an iPSC-Derived Neuron Model of CLN3 Disease

“…A major pitfall in developing pharmacological intervention for the NCLs is the limited repertoire of in vitro models suitable for the screening of novel neuroprotective drug candidates. The emergence of iPSC-based models has revolutionized the field of disease modeling, resulting in deeper insight into the pathological mechanisms of several neurological diseases including Batten disease (28,36,40). In this study, we are the first to report the successful differentiation of neurons and BMECs from a patient-derived iPSC line originating from a 21-year-old male bearing a 1kb deletion in the CLN3 gene and heterozygous for E13 c.988G>T, p.Val330Phe mutation, using established protocols (44,45).…”

“…These NSCs were used to evaluate the effect of two small molecules versus enzyme replacement therapy (39). Neurons differentiated from CLN5 patient-derived iPSCs expressed accumulation of autofluorescent storage material and subunit C of mitochondrial ATP synthase and are being used to further understand the mechanisms of CLN5 disease (40). An adeno-associated adenovirus serotype 2 (AAV2) carrying the full-length coding sequence of CLN3 was shown to be effective in restoring fulllength CLN3 protein in CLN3 patient iPSC-derived retinal neurons (41).…”