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Purpose Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of rare inherited neurodegenerative disorders caused by mutations in one of 13 ceroid lipofuscinosis neuronal ( CLN ) genes. The diseases share a common set of symptoms, including motor and cognitive dysfunction, progressive loss of vision, and seizure activity. A naturally occurring model of CLN5 NCL exists in New Zealand Borderdale sheep, which exhibit similar clinical disease and post‐mortem pathology to the human disease. Recent trials of concurrent intracerebroventricular and intravitreal gene therapy in sheep with CLN5 disease confirmed the therapeutic efficacy of this approach. Given the documented natural history of brain volume changes, detected by MRI, in sheep with CLN5 disease, the current study sought to utilize MRI as both a longitudinal readout and cross‐sectional measure of therapeutic efficacy in treated sheep. Method Sheep treated at a pre‐symptomatic timepoint underwent five T1‐weighted structural MRI scans between 5 and 18 months of age. Sheep treated at early and advanced symptomatic disease stages underwent a single MRI at 18 months of age. All scans from treated sheep were compared to historical healthy control and affected untreated sheep at each age. Finding Pre‐symptomatic treated sheep showed growth in intracranial volume at a comparable rate to healthy control sheep over the course of the study. Whilst grey matter volume decreased and cerebrospinal fluid volume increased in treated sheep, this was to a much smaller degree than in untreated affected sheep. The majority of the cortical regions assessed showed stable volumes over the course of the study, with the notable exception of the cerebellum. Both early and advanced symptomatic treated sheep showed intracranial volumes comparable to untreated affected sheep at 18 months of age. However, when individual tissue types were assessed, grey and white matter were significantly larger, and cerebrospinal fluid was significantly smaller in early symptomatic sheep compared to untreated affected sheep, while the same volumes in advanced symptomatic treated sheep were comparable to untreated affected sheep. Cortical regions assessed showed an age‐at‐treatment and dose effect. Conclusion This study has demonstrated that MRI, a clinically relevant outcome measure, can be successfully utilized to assess therapeutic efficacy in a large animal model of CLN5 NCL, both in a longitudinal study and a cross‐sectional study when robust natural history data is available for comparison.

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.

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.

Neuronal ceroid lipofuscinoses (NCL) belong to a group of inherited neurodegenerative diseases characterized by psychomotor regression, seizures, and visual impairment, resulting from intracellular accumulation of lipofuscin. CLN5, a subtype typically manifesting between ages 4 to 17, is particularly rare in non‐Finnish populations. Here, we report the first Japanese case of CLN5 in a 12‐year‐old girl with progressive myoclonic epilepsy and psychomotor regression. Initial assessments for common metabolic disorders, including GM2 gangliosidosis, were inconclusive. Trio‐based genome sequencing (GS) identified a novel homozygous pathogenic variant in CLN5, confirming the diagnosis at 10 years and 6 months of age. Subsequent evaluations revealed progressive cerebral and cerebellar atrophy and vision loss. This case underscores the importance of GS in diagnosing rare neurodegenerative diseases and highlights the clinical spectrum of CLN5, which presents with rapid neurological decline. Expanding diagnostic frameworks with genetic testing is critical for early diagnosis and potential therapeutic interventions in CLN5 and related NCL disorders. Key Clinical Message Through the first Japanese case of CLN5, comprehensive genetic testing, such as genome sequencing, proved to be crucial for the accurate and prompt diagnosis of progressive myoclonic epilepsy, emphasizing the need to include rare neurological disorders like CLN5 in differential diagnoses.

Neuronal ceroid lipofuscinosis (NCL) is one of the most common causes of childhood dementia. NCL type 5 is characterized by epileptic seizures, cognitive decline, and progressive vision loss. Whole exome sequencing was performed, and the identified variant was confirmed by Sanger sequencing. Despite various therapeutic regimens, including novel approaches, seizure control could not be achieved. The disease was caused by a previously undescribed pathogenic variant CLN5 (NM_006493.4):c.368del (p.Arg123LysfsTer4). This is the first known case of NCL type 5 in Russia. Unusually, the patient also had a cervical lymphangioma requiring separate medical and surgical intervention. This case report contributes to our understanding of the natural history of CLN5-associated NCL and may support the development of gene therapy approaches for its treatment.

Background This work investigated the role of HAGLROS in laryngeal cancer (LC). Methods HAGLROS expression in the head and neck squamous cell carcinoma (HNSC), target miRNAs of HAGLROS, target mRNAs of miR‐138‐5p, and the binding sites of HAGLROS and miR‐138‐5p or CLN5 and miR‐138‐5p were predicted through bioinformatics. HAGLROS, miR‐138‐5p, CLN5, Bcl‐2, and Bax levels were detected by qRT–PCR and Western blot. The biological functions of LC cells were assessed through CCK‐8, colony formation assays, transwell assay, and flow cytometry assay. The targeting relationship between HAGLROS and miR‐138‐5p or CLN5 and miR‐138‐5p was confirmed by dual luciferase gene reporter analysis. Results HAGLROS was upregulated in LC. HAGLROS‐specific small interfering RNA (Si‐HAGLROS) inhibited the viability, proliferation, migration, and invasion while increased the apoptosis in LC cells. MiR‐138‐5p was a target of HAGLROS and the miR‐138‐5p inhibitor reversed the effects of si‐HAGLROS on LC cells. CLN5 was a target of miR‐138‐5p. MiR‐138‐5p inhibitor raised the viability, migration and invasion, and Bcl‐2 expression while declined Bax expression in LC cells, with si‐CLN5 performing the opposite effects and reversing the effects of miR‐138‐5p inhibitor. Conclusion Silenced HAGLROS restrained the LC cells' abilities to proliferate, migrate, and invade as well as facilitated apoptosis in LC via miR‐138‐5p/CLN5 axis. HAGLROS was upregulated in LC and it promoted the proliferation and invasion as well as inhibited the apoptosis of LC cells via miR‐138‐5p/CLN5 axis.

Dendrogenin A (DDA) is a cholesterol‐derived antitumour metabolite that promotes the secretion of immunogenic antitumour exosomes (DDA‐sEV) enriched in bis(monoacylglycero)phosphate (BMP). BMP is a phospholipid specific to late endosomes and lysosomes, where it plays a crucial role in lipid degradation, regulates the fate of endosomal cholesterol, and contributes to intraluminal vesicle formation. Dysregulation of BMP biosynthesis is associated with multiple diseases. Here, we show that the DDA/LXRβ complex activates the transcription and activity of phospholipase D (PLD) and CLN5, two enzymes involved in BMP biosynthesis. Inhibition of PLD in DDA‐treated tumour cells reduces BMP levels in DDA‐sEV, impairs their release, and their antitumour immune activity. Blocking BMP on DDA‐sEV with a specific antibody abolishes their antitumour reponse, prevents the recruitment of activated dendritic cells (DC) and T cells into tumours, and decreases mouse survival. This blockade also impairs DDA‐sEV uptake by immature DC (iDC) and hinders DC maturation and Th1 T cell activation. Notably, neutralising the BMP‐presenting receptor on iDC inhibits DDA‐sEV uptake and DC maturation. Treatment of iDC with free BMP induces their functional maturation, confirming BMP as a key immune activator. Furthermore, BMP‐containing DDA‐sEV enhance the efficacy of anti‐PD‐1 therapy in melanoma. Targeting LXRβ with DDA represents an innovative strategy to stimulate anticancer immunity by increasing BMP levels in tumours and sEV. Dendrogenin A stimulates, via LXRβ, the expression and activity of enzymes responsible for the biosynthesis of the phospholipid BMP. BMP is a key determinant of the antitumour immunogenicity of exosomes secreted by DDA‐treated melanoma and triple‐negative breast cancer cells and enhances mouse survival and anti‐PD‐1 therapy in melanoma.

CLN5 disease (MIM: 256731) represents a rare late-infantile form of neuronal ceroid lipofuscinosis (NCL), caused by mutations in the CLN5 gene that encodes the CLN5 protein (CLN5p), whose physiological roles stay unanswered. No cure is currently available for CLN5 patients and the opportunities for therapies are lagging. The role of lysosomes in the neuro-pathophysiology of CLN5 disease represents an important topic since lysosomal proteins are directly involved in the primary mechanisms of neuronal injury occurring in various NCL forms. We developed and implemented a lysosome-focused, label-free quantitative proteomics approach, followed by functional validations in both CLN5-knockout neuronal-like cell lines and Cln5−/− mice, to unravel affected pathways and modifying factors involved in this disease scenario. Our results revealed a key role of CLN5p in lipid homeostasis and sphingolipid metabolism and highlighted mutual NCL biomarkers scored with high lysosomal confidence. A newly generated cln5 knockdown zebrafish model recapitulated most of the pathological features seen in NCL disease. To translate the findings from in-vitro and preclinical models to patients, we evaluated whether two FDA-approved drugs promoting autophagy via TFEB activation or inhibition of the glucosylceramide synthase could modulate in-vitro ROS and lipid overproduction, as well as alter the locomotor phenotype in zebrafish. In summary, our data advance the general understanding of disease mechanisms and modifying factors in CLN5 disease, which are recurring in other NCL forms, also stimulating new pharmacological treatments.

Mutations in CLN5 cause a subtype of neuronal ceroid lipofuscinosis (NCL) called CLN5 disease. While the precise role of CLN5 in NCL pathogenesis is not known, recent work revealed that the protein has glycoside hydrolase activity. Previous work on the Dictyostelium discoideum homolog of human CLN5, Cln5, revealed its secretion during the early stages of development and its role in regulating cell adhesion and cAMP-mediated chemotaxis. Here, we used Dictyostelium to examine the effect of cln5 -deficiency on various growth and developmental processes during the life cycle. During growth, cln5 – cells displayed reduced cell proliferation, cytokinesis, viability, and folic acid-mediated chemotaxis. In addition, the growth of cln5 – cells was severely impaired in nutrient-limiting media. Based on these findings, we assessed autophagic flux in growth-phase cells and observed that loss of cln5 increased the number of autophagosomes suggesting that the basal level of autophagy was increased in cln5 – cells. Similarly, loss of cln5 increased the amounts of ubiquitin-positive proteins. During the early stages of multicellular development, the aggregation of cln5 – cells was delayed and loss of the autophagy genes, atg1 and atg9 , reduced the extracellular amount of Cln5. We also observed an increased amount of intracellular Cln5 in cells lacking the Dictyostelium homolog of the human glycoside hydrolase, hexosaminidase A (HEXA), further supporting the glycoside hydrolase activity of Cln5. This observation was also supported by our finding that CLN5 and HEXA expression are highly correlated in human tissues. Following mound formation, cln5 – development was precocious and loss of cln5 affected spore morphology, germination, and viability. When cln5 – cells were developed in the presence of the autophagy inhibitor ammonium chloride, the formation of multicellular structures was impaired, and the size of cln5 – slugs was reduced relative to WT slugs. These results, coupled with the aberrant autophagic flux observed in cln5 – cells during growth, support a role for Cln5 in autophagy during the Dictyostelium life cycle. In total, this study highlights the multifaceted role of Cln5 in Dictyostelium and provides insight into the pathological mechanisms that may underlie CLN5 disease.

Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene ( CLN5 ). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.