2026-06-18 | Thapsigargin-induced autophagic flux impairment and inflammation are potentiated by CLN3 deficiency and alleviated by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in human ARPE-19 cells.
Juvenile neuronal lipofuscinosis (JNCL) is a rare disease caused by mutations in the CLN3 gene. It leads to early vision loss mediated by retinal degeneration. Impaired autophagosomal-lysosomal degradation is a major hallmark of JNCL pathology, and neuroinflammation has also been postulated to play a role in its pathogenesis. Thapsigargin, a selective inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase, inhibits autophagy, leading to an accumulation of autophagosomes/autophagophores in cells. Cells with defective CLN3 protein function have been found to be particularly sensitive to the anti-autophagic effects of thapsigargin. Here, we characterized the effects of thapsigargin on inflammatory cytokines and autophagic markers in ARPE-19 cells using ELISA and western blotting. We further examined these effects in cells deficient in CLN3 function by exposing the cells to CLN3 siRNA and testing whether the effects of thapsigargin could be modulated by the well-known autophagy activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Thapsigargin induced the accumulation of LC3 and p62/SQSTM1, consistent with impaired autophagic flux in ARPE-19 cells. Additionally, we observed that thapsigargin possessed pro-inflammatory potential, as it induced the release of IL-6 in ARPE-19 cells, no inflammasome activation was detected. Both effects were enhanced by CLN3 siRNA and alleviated by AICAR. In conclusion, thapsigargin-induced impaired autophagic flux and the accompanying inflammatory response are more pronounced in CLN3-deficient ARPE-19 cells, indicating that loss of CLN3 function affects both autophagy and inflammatory signaling.
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2026-05-19 | Mania in Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 Disease): A Rare Neuropsychiatric Presentation in an Adolescent.
Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease) is a rare autosomal recessive neurodegenerative lysosomal storage disorder characterized by childhood-onset progressive visual loss, epilepsy, and cognitive decline. Although behavioral and emotional symptoms are frequently reported, manic episodes remain rarely characterized within a structured diagnostic framework. We present a 16-year-old girl with progressive visual impairment and epilepsy who developed a manic episode with psychotic features meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, including decreased need for sleep, increased goal-directed activity, hypersexuality, pressured speech, and hallucinations. Genetic testing using whole exome sequencing identified a homozygous likely pathogenic variant in CLN3 (c.898C>T), which was also identified in her affected sibling, further supporting the diagnosis of JNCL. The patient showed significant clinical improvement with antipsychotic treatment and multidisciplinary follow-up. This report delineates the neuropsychiatric spectrum associated with CLN3 disease and supports the need for systematic mood symptom monitoring in affected adolescents. These findings should be interpreted as hypothesis-generating, and further studies are needed to clarify the underlying mechanisms.
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2026-05-18 | PPARα and RXRα in the regulation of neuronal ceroid lipofuscinosis genes: implications for Batten disease therapy.
Neuronal ceroid lipofuscinosis or Batten disease comprises a category of autosomal recessive neurodegenerative disorders that primarily affect children. Mutations in different genes lead to different forms of neuronal ceroid lipofuscinoses (CLN1-14). At present, there is no established therapy to cure most of the neuronal ceroid lipofuscinoses and the treatments are symptomatic. Enzyme replacement therapy, gene therapy, stem cell transplantation, and pharmacological chaperone therapy are being tested in different animal models and human patients. Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear hormone receptor superfamily, which along with its transcription partner retinoid X receptor alpha (RXRα) regulates the expression of their target genes. This review highlights the potential role of PPARα and RXRα in the regulation of CLN genes. Here, using the MatInspector program of the Genomatix software, we performed promoter analyses of all CLN genes and observed that most of the CLN genes harbor one or more potential binding sites for PPAR and RXR in their promoter region. We further grouped them according to a binding prediction of the transcription factors to indicate high affinity binding of PPAR to CLN2, CLN3, CLN4, CLN5, CLN7, CLN10, CLN11, CLN12, and CLN14. On the other hand, we observed high affinity binding of RXR to CLN1, CLN3, CLN6, CLN7, CLN8, CLN10, and CLN13. Since PPARα and RXRα have been demonstrated to control the transcription of CLN2 gene, our current promoter analysis findings highlight a possible treatment strategy for neuronal ceroid lipofuscinoses using agonists of PPARα and RXRα.
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