Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 3, 2023

Abstract Batten disease, one of the most devastating types neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3 . Here, we show that a vesicular trafficking hub connecting Golgi and lysosome compartments. Proteomic analysis reveals interacts with several endo-lysosomal proteins, including cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates targeting enzymes to lysosomes. depletion results mis-trafficking CI-M6PR, mis-sorting enzymes, defective autophagic reformation. Conversely, overexpression promotes formation multiple tubules, are autophagy CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal functions as link between M6P-dependent reformation pathway, explaining global impairment function disease.

Язык: Английский

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Glycerophosphodiesters inhibit lysosomal phospholipid catabolism in Batten disease

Molecular Cell, Год журнала: 2024, Номер 84(7), С. 1354 - 1364.e9

Опубликована: Март 5, 2024

Batten disease, the most prevalent form of neurodegeneration in children, is caused by mutations CLN3 gene, which encodes a lysosomal transmembrane protein. loss leads to significant accumulation glycerophosphodiesters (GPDs), end products glycerophospholipid catabolism lysosome. Despite GPD storage being robustly observed upon loss, role GPDs neuropathology remains unclear. Here, we demonstrate that act as potent inhibitors lysosome using human cell lines and mouse models. Mechanistically, bind competitively inhibit phospholipases PLA2G15 PLBD2, establish possess phospholipase B activity. effectively rate-limiting lysophospholipase activity these phospholipases. Consistently, lysosomes CLN3-deficient cells tissues accumulate toxic lysophospholipids. Our work establishes material disease directly disrupts lipid homeostasis, suggesting clearance potential therapeutic approach this fatal disease.

Язык: Английский

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Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease)

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Фев. 16, 2022

The neuronal ceroid lipofuscinoses (NCLs), also referred to as Batten disease, are a family of neurodegenerative diseases that affect all age groups and ethnicities around the globe. At least dozen NCL subtypes have been identified each linked mutation in distinct lipofuscinosis (CLN) gene. Mutations CLN genes cause accumulation autofluorescent lipoprotein aggregates, called lipofuscin, neurons other cell types outside central nervous system. mechanisms regulating this material not entirely known. encode cytosolic, lysosomal, integral membrane proteins associated with variety cellular processes, accumulated evidence suggests they participate shared or convergent biological pathways. Research across non-mammalian mammalian model systems clearly supports an effect gene mutations on autophagy, suggesting autophagy plays essential role development progression NCLs. In review, we summarize research linking pathway NCLs guide future work further elucidates contribution altered pathology.

Язык: Английский

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Speech, Language and Non‐verbal Communication in CLN2 and CLN3 Batten Disease

Journal of Inherited Metabolic Disease, Год журнала: 2025, Номер 48(1)

Опубликована: Янв. 1, 2025

Язык: Английский

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Characterisation of sleep in a mouse model of CLN3 disease revealed sex‐specific sleep disturbances

Journal of Sleep Research, Год журнала: 2025, Номер unknown

Опубликована: Янв. 28, 2025

The neuronal ceroid lipofuscinoses (NCLs) are a group of recessively inherited neurodegenerative diseases characterizsed by lysosomal storage fluorescent materials. CLN3 disease, or juvenile Batten is the most common NCL that caused mutations in Ceroid Lipofuscinosis, Neuronal 3 (CLN3) gene. Sleep disturbances among symptoms associated with disease deteriorate patients' life quality, yet this understudied and has not been delineated animal models disease. current study utilised PiezoSleep, non-invasive, automated piezoelectric motion sensing system, to classify sleep wakefulness Cln3Δex1-6/Δex1-6 (Cln3KO) mouse model age- sex-matched wild-type (WT) controls. sleep-wake classification PiezoSleep was found be about 90% accurate when validated against simultaneous polysomnographic recordings including electroencephalography (EEG) electromyography (EMG) small cohort WT Cln3KO mice. Our large revealed abnormalities during light period male mice compared mice, more subtle differences female dark characterisation aligns seen patients serves as basis continue examining commonly reported for other NCLs. As first capturing our work will facilitate future studies into potential mechanism behind treatment strategies.

Язык: Английский

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Mechanisms and functions of lysosomal lipid homeostasis

Cell chemical biology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Forward Genetics-Based Approaches to Understanding the Systems Biology and Molecular Mechanisms of Epilepsy

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5280 - 5280

Опубликована: Март 9, 2023

Epilepsy is a highly prevalent, severely debilitating neurological disorder characterized by seizures and neuronal hyperactivity due to an imbalanced neurotransmission. As genetic factors play key role in epilepsy its treatment, various genomic technologies continue dissect the causes of this disorder. However, exact pathogenesis not fully understood, necessitating further translational studies condition. Here, we applied computational silico approach generate comprehensive network molecular pathways involved epilepsy, based on known human candidate genes their established interactors. Clustering resulting identified potential interactors that may contribute development revealed functional associated with disorder, including those related hyperactivity, cytoskeletal mitochondrial function, metabolism. While traditional antiepileptic drugs often target single mechanisms recent suggest targeting downstream as alternative efficient strategy. many have yet been considered promising targets for treatment. Our study calls research into complexity underlying aiming develop more effective treatments novel putative

Язык: Английский

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Early postnatal administration of an AAV9 gene therapy is safe and efficacious in CLN3 disease

Frontiers in Genetics, Год журнала: 2023, Номер 14

Опубликована: Март 24, 2023

CLN3 disease, caused by biallelic mutations in the gene, is a rare pediatric neurodegenerative disease that has no cure or modifying treatment. The development of effective treatments been hindered lack etiological knowledge, but gene replacement emerged as promising therapeutic platform for such disorders. Here, we utilize mouse model to test safety and efficacy cerebrospinal fluid-delivered AAV9 therapy with study design optimized translatability. In this model, postnatal day one administration virus resulted robust expression human throughout CNS over 24-month duration study. A range histopathological behavioral parameters were assayed, consistently persistently rescuing number hallmarks while being safe well-tolerated. Together, results show great promise translation into clinic, prompting launch first-in-human clinical trial (NCT03770572).

Язык: Английский

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The involvement of Purkinje cells in progressive myoclonic epilepsy: Focus on neuronal ceroid lipofuscinosis

Neurobiology of Disease, Год журнала: 2023, Номер 185, С. 106258 - 106258

Опубликована: Авг. 11, 2023

The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and neurological deterioration with cerebellar involvement. They include storage like Gaucher disease, Lafora forms neuronal ceroid lipofuscinosis (NCL). To date, 13 NCLs have been reported (CLN1-CLN8, CLN10-CLN14), associated mutations in different genes. These forms, which affect both children adults, cognitive motor impairments, most cases visual loss. In NCLs, as other PMEs, central nervous system (CNS) neurodegeneration is widespread involves subpopulations neurons. One the affected regions cortex, where non-motor information processed transmitted to deep nuclei through axons Purkinje cells (PCs). PCs, being GABAergic, an inhibitory effect on their target neurons, provide only output cerebellum. Degeneration PCs has linked impairments seizures. Seizures occur when some insult upsets normal balance CNS between excitatory impulses, causing hyperexcitability. Here we review role epilepsy onset progression following PME-related particular, focus involvement seizure phenotype highlighting findings from case reports studies animal models can be PC

Язык: Английский

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Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease

EBioMedicine, Год журнала: 2023, Номер 92, С. 104628 - 104628

Опубликована: Май 26, 2023

The most common form of neuronal ceroid lipofuscinosis (NCL) is juvenile CLN3 disease (JNCL), a currently incurable neurodegenerative disorder caused by mutations in the gene. Based on our previous work and premise that affects trafficking cation-independent mannose-6 phosphate receptor its ligand NPC2, we hypothesised dysfunction leads to aberrant accumulation cholesterol late endosomes/lysosomes (LE/Lys) JNCL patients' brains.An immunopurification strategy was used isolate intact LE/Lys from frozen autopsy brain samples. isolated samples patients were compared with age-matched unaffected controls Niemann-Pick Type C (NPC) patients. Indeed, NPC1 or NPC2 result NPC samples, thus providing positive control. lipid protein content then analysed using lipidomics proteomics, respectively.Lipid profiles profoundly altered controls. Importantly, accumulated comparable extent than Lipid similar patients, except for levels bis(monoacylglycero)phosphate (BMP). Protein detected appeared identical, NPC1.Our results support lysosomal storage disorder. Our findings also share pathogenic pathways leading lipids proteins, suggest treatments available may be beneficial This opens new avenues further mechanistic studies model systems possible therapeutic interventions this disorder.San Francisco Foundation.

Язык: Английский

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