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Acidic phospholipases in cultured human fibroblasts: deficiency of phospholipase C in Niemann-Pick disease.

Radioactive phosphatidyl choline substrates specifically labeled in the one position or two position fatty acid were used to establish condi … C. The activities examined were within the normal range in fibroblasts from patients with neuronal ceroid lipofuscinosis, sea blue histiocyte disease and selected uncharacterized degenerative diseases.

[EEG changes in the course of progressive cerebral disorders in children (author's transl)].

This survey presents EEG-data on the following disorders: Globoid-cell leucodystrophy (Krabbe), Metachromatic Leukodystrophy, GM2 Gangliosidosis I (Tay-Sachs), Neuronal Ceroidlipofuscinosis. During Krabbe's disease the background activity of the EEG slows down, multifocal and generalized hypersynchroneous activity (HSA) appears, in the final stage hypsarrythmia is found occasionally. In contrast HSA during Sulfatide lipidosis appears only in the final stages. The EEG changes in Tay Sachs disease are minimal in the beginning; later only high amplitude slowing and especially focal abnormalities …

Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.

According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(…

Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip.

Mutations in the tripeptidyl peptidase 1 (TPP1) gene lead to neuronal ceroid lipofuscinosis type 2 (CLN2), characterized by lysosomal accumulation of lipofuscins predominantly in the brain and retina. The ocular phenotype is characterized by outer retinal degeneration that leads to vision loss. Leveraging human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs), retinal pigmented epithelial cells, and the retina-on-chip system, we establish an in vitro CLN2 model that recreates the principal histological hallmarks, namely the accumulation of subunit C of mitochondrial ATP sy…

Prodromal pathogenesis of CLN7 Batten Disease revealed by multimodal biomarkers in macaques.

Neuronal ceroid lipofuscinosis type 7 (CLN7) is a devastating paediatric neurodegenerative disorder with no cure and limited natural history data to guide therapeutic development. Here, we present the first multimodal characterization of prodromal and early-stage CLN7 disease in Japanese macaques carrying a spontaneous CLN7 -/- mutation. Using structural T2-weighted MRI for volumetry, [18F]FDG PET for glucose metabolism, and [11C]PBR28 PET for neuroinflammation, we observed region-dependent patterns in volumetric, molecular, and metabolic alterations. MRI confirmed the presence of disease-asso…

S-ациляция и нейроинфламмация: терапевтический потенциал zDHC и модуляции децилазы.

Нейроинфламмация является отличительной чертой многих нейродегенеративных заболеваний, включая болезнь Альцгеймера, болезнь Паркинсона и Хантингтона, множественный склероз и инфантильный нейроидальный липофусциноз. Важным регулятором этих процессов является динамическое белковое С-асилирование, обратимое липидное послепереходное изменение. С-ациляция стимулируется zDHC palmitoil aciltransfases, а удаление ацильных групп - ацилпротеиновыми тиоэстеразами. С-асилация контролирует локализацию, стабильность и функцию около 48% всех белков в нервной системе, включая синаптические скафольды, ионные к

Совпадение в аннотации оригинала
Neuroinflammation is a hallmark of many neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, and infantile neuronal ceroid lipofuscinosis. Dynamic protein S-acylation, a reversible lipid post-translational modification, is an important regulator in these processes. S-acylation is catalysed by the zDHHC …

TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells.

Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of the lysosomal ion channel TRPML1 has previously been shown to be beneficial in several neurodegenerative disease models. Here, we tested whether TRPML1 activation rescues disease-associated phenotypes in CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show lysosomal storage of mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), and glycerophosphodiesters (GPDs), whereas lysosomal bi…

The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis.

Pseudomonas aeruginosa can cause nosocomial infections, especially in ventilated or cystic fibrosis patients. Highly pathogenic isolates exp … cytoplasm. DNAJC5 mutations preventing vesicle trafficking (previously identified in adult neuronal ceroid lipofuscinosis, a human congenital disease) inhibit ExoU-dependent cell lysis. Our results suggest that, once injected into the host cytoplasm, ExoU docks to DNAJC5-positive secretory vesicles to reach the plasma membrane, where it can exert its pho …

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases.

Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mous … t canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and …

Discovery of a CLN7 model of Batten disease in non-human primates.

We have identified a natural Japanese macaque model of the childhood neurodegenerative disorder neuronal ceroid lipofuscinosis, commonly known as Batten Disease, caused by a homozygous frameshift mutation in the CLN7 gene (CLN7-/-). Affected macaques display progressive neurological deficits including visual impairment, tremor, incoordination, ataxia and impaired balance. Imaging, functional and pathological studies revealed that CLN7-/- macaques have reduced retinal thickness and retinal function early in disease, followed by profound cerebral and cerebellar atrophy that progresses over a fiv…

Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.

Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL) and Niemann-Pick type C (NPC), and is implicated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-TDP) with progranulin (PGRN) deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distingui…

Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin.

Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes is still not clear. Here we report a novel pathway for lysosomal delivery of PGRN. We found that prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotei…

The large conductance, calcium-activated K+ (BK) channel is regulated by cysteine string protein.

Large-conductance, calcium-activated-K(+) (BK) channels are widely distributed throughout the nervous system, where they regulate action potential duration and firing frequency, along with presynaptic neurotransmitter release. Our recent efforts to identify chaperones that target neuronal ion channels have revealed cysteine string protein (CSPα) as a key regulator of BK channel expression and current density. CSPα is a vesicle-associated protein and mutations in CSPα cause the hereditary neurodegenerative disorder, adult-onset autosomal dominant neuronal ceroid lipofuscinosis (ANCL). CSPα null…

Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA).

Regulation of iron metabolism is crucial: both iron deficiency and iron overload can cause disease. In recent years, our understanding of th … ent NBIA disorders and other diseases including spastic paraplegias, leukodystrophies, and neuronal ceroid lipofuscinosis. Lewy body pathology was confirmed in some clinical subtypes (C19orf12-associated neurodegeneration and PLAN). Research aims at disentangling the various NBIA genes and their related pathways to move towards pathogenesis-targeted ther …

Lentiviral-mediated gene transfer to the sheep brain: implications for gene therapy in Batten disease.

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are inherited neurodegenerative lysosomal storage diseases with common clinical features of blindness and seizures culminating in premature death. Gene-therapy strategies for these diseases depend on whether the missing activity is a secreted lysosomal protein taken up by neighboring cells, or an intramembrane protein that requires careful targeting. Therapies are best developed in animal models with large complex human-like brains. Lentiviral-mediated gene delivery to neural cell cultures from normal sheep and sheep affected with an NC…

Adipocytes participate in storage in α-galactosidase deficiency (Fabry disease).

Ultrastructural and histochemical studies of bioptic and postmortem tissue samples from ten Fabry hemizygotes showed lysosomal storage in adipocytes as a constant feature of the classic phenotype of α-galactosidase (GLA) deficiency. The storage was represented by a crescent-shaped line of storage lysosomes of varying thicknesses restricted to the perinuclear subplasmalemmal area. The ultrastructure of the storage lysosomes was dominated by concentric lipid membranes modified by simultaneous deposition of autofluorescent ceroid. Storage was widely expressed in adipose tissue. The number of stor…

Newborn screening for hermansky-pudlak syndrome type 3 in Puerto Rico.

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by albinism, mucocutaneous bleeding, and storage of ceroid material in macrophages. Patients who are not easily identified by physical characteristics (mostly HPS-3 patients) may have hemorrhagic complications with trauma or surgery. OBJECTIVE: To determine the prevalence of HPS-3 in Puerto Rican newborns using DNA pooling technique. DESIGN/METHODS: Twelve percent of annual Puerto Rican births were tested randomly by polymerase chain reaction for the HPS-3 mutation, using pooled DNA extracted from dr…

[Neurological presentations of lysosomal diseases in adult patients].

Lysosomal diseases represent a large group of genetic storage disorders characterized by a defect in the catabolism of complex molecules wit … chiatric-like diseases (GM1 and GM2 gangliosidoses, Niemann Pick type C disease, sialidosis type I, ceroid-lipofuscinosis, mucopolysaccharidosis type III); (3) multisystemic diseases (Gaucher's disease, Fabry's disease, alpha and B mannosidosis, Niemann Pick disease type B, fucosidosis, Schindler/Kanzaki disease, and mucopolysaccharidosis type I and II. …

Over-expression of CLN3P, the Batten disease protein, inhibits PANDER-induced apoptosis in neuroblastoma cells: further evidence that CLN3P has anti-apoptotic properties.

Juvenile neuronal ceroid-lipofuscinosis (JNCL) or Batten/Spielmeyer-Vogt-Sjogren disease (OMIM #204200) is one of a group of nine clinically related inherited neurodegenerative disorders (CLN1-9). JNCL results from mutations in CLN3 on chromosome 16p12.1. The neuronal loss in Batten disease has been shown to be due to a combination of apoptosis and autophagy suggesting that CLN3P, the defective protein, may have an anti-neuronal death function. PANDER (PANcreatic-DERived factor) is a novel cytokine that was recently cloned from pancreatic islet cells. PANDER is specifically expressed in the pa…

Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons.

Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons. We generated Ppt1Deltaex4 mice by a targeted deletion of exon 4 of the mouse Ppt1 gene. Similar to the clinical phenotype, the homozygous mutants show loss of vision from the age of 8 weeks, seizures after 4 months and paralysis of hind limbs at the age of 5 months. Autopsy revealed a dramatic loss of brain mass and histopathology demonstrated accumulation of autofluorescent granular osmiophilic deposits (GROD…