scholarly journals Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material

2010 ◽  
Vol 428 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Su Xu ◽  
David E. Sleat ◽  
Michel Jadot ◽  
Peter Lobel
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Subcellular Fractionation ◽  
Acidic Protein ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Mitochondrial Atp Synthase

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease of children caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl peptidase 1. LINCL is characterized by lysosomal accumulation of storage material of which only a single protein component, subunit c of mitochondrial ATP synthase, has been well established to date. Identification of other protein constituents of the storage material could provide useful insights into the pathophysiology of disease and the natural substrates for TPP1. We have therefore initiated a proteomic analysis of storage material in brain from a LINCL mouse model. One protein, GFAP (glial fibrillary acidic protein), was found to be elevated in the LINCL mice compared with normal controls in both isolated storage bodies and a lysosome-enriched subcellular fraction that contains storage material. To determine whether GFAP accumulates within the lysosome in LINCL, we examined its intracellular distribution using subcellular fractionation and morphological methods. These experiments demonstrate that GFAP is not a component of the storage material in LINCL, suggesting that reports of GFAP storage in other NCLs may need to be re-examined. A number of other proteins were elevated in the storage material and/or lysosome-enriched fraction from the LINCL mice, but it remains unclear whether these proteins are true constituents of the storage material or, like GFAP, whether they associate with this material upon purification.

scholarly journals Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

2017 ◽  
Vol 9 (385) ◽  
pp. eaah5642 ◽  
Author(s):  
Michael E. Ward ◽  
Robert Chen ◽  
Hsin-Yi Huang ◽  
Connor Ludwig ◽  
Maria Telpoukhovskaia ◽  
...  
Keyword(s):  
Storage Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Disease Process ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Disease Mechanisms ◽  
Mutation Carriers ◽  
Dementia Onset

Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

scholarly journals Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2813
Author(s):  
Antje Banning ◽  
Ritva Tikkanen
Keyword(s):  
Small Molecules ◽  
Splice Site ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage Disorders ◽  
Specific Gene ◽  
Lysosomal Storage ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Splicing Defects ◽  
Storage Disorders

Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing TPP1 gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.

Infantile neuronal ceroid lipofuscinosis: Isolation of storage material

Neurology ◽  
1982 ◽  
Vol 32 (9) ◽  
pp. 1035-1035 ◽  
Author(s):  
J. Palo ◽  
I. Elovaara ◽  
M. Haltia ◽  
N. M. K. Ng Ying Kin ◽  
L. S. Wolfe
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Storage Material ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis

Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosis

2001 ◽  
Vol 357 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Li LIN ◽  
Peter LOBEL
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Chinese Hamster Ovary Cells ◽  
Gel Filtration ◽  
Chinese Hamster ◽  
Ovary Cells ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Enzyme Replacement ◽  
Ceroid Lipofuscinosis ◽  
Mitochondrial Atp Synthase ◽  
Mannose 6 Phosphate

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal recessive childhood disease caused by mutations in the CLN2 gene, which encodes the lysosomal enzyme tripeptidyl peptidase I. As a step towards understanding the protein and developing therapeutics for the disease, we have produced and characterized recombinant human CLN2 (ceroid lipofuscinosis, neuronal 2) protein from Chinese-hamster ovary cells engineered to secrete high levels of the enzyme. The protein was secreted as an inactive soluble proenzyme of ≈ 65kDa that appears as a monomer by gel filtration. Upon acidification, the protein is processed to mature form and acquires activity. The enzyme is efficiently delivered to the lysosomes of LINCL fibroblasts by mannose 6-phosphate-receptor-mediated endocytosis (EC50≈ 2nM), where it remains active for long periods of time (t1/2≈ 12 days). In addition, the enzyme is taken up by rat cerebellar granule neurons by mannose 6-phosphate-dependent and -independent mechanisms. Treatment of LINCL fibroblasts with recombinant CLN2 protein restores normal enzyme activity and ameliorates accumulation of the major storage protein, mitochondrial ATP synthase subunit c.

scholarly journals Dipeptidyl-peptidase I does not functionally compensate for the loss of tripeptidyl-peptidase I in the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis

2008 ◽  
Vol 415 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Kwi-Hye Kim ◽  
Christine T. Pham ◽  
David E. Sleat ◽  
Peter Lobel
Keyword(s):  
Neurodegenerative Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Dipeptidyl Peptidase ◽  
The Body ◽  
Peripheral Tissues ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Tripeptidyl Peptidase ◽  
The Brain

LINCL (late-infantile neuronal ceroid lipofuscinosis) is a fatal neurodegenerative disease resulting from mutations in the gene encoding the lysosomal protease TPPI (tripeptidyl-peptidase I). TPPI is expressed ubiquitously throughout the body but disease appears restricted to the brain. One explanation for the absence of peripheral pathology is that in tissues other than brain, other proteases may compensate for the loss of TPPI. One such candidate is another lysosomal aminopeptidase, DPPI (dipeptidyl-peptidase I), which appears to have overlapping substrate specificity with TPPI and is expressed at relatively low levels in brain. Compensation for the loss of TPPI by DPPI may have therapeutic implications for LINCL and, in the present study, we have investigated this possibility using mouse genetic models. Our rationale was that if DPPI could compensate for the loss of TPPI in peripheral tissues, then its absence should exacerbate disease in an LINCL mouse model but, conversely, increased CNS (central nervous system) expression of DPPI should ameliorate disease. By comparing TPPI and DPPI single mutants with a double mutant lacking both proteases, we found that the loss of DPPI had no effect on accumulation of storage material, disease severity or lifespan of the LINCL mouse. Transgenic expression of DPPI resulted in a ∼2-fold increase in DPPI activity in the brain, but this had no significant effect on survival of the LINCL mouse. These results together indicate that DPPI cannot functionally compensate for the loss of TPPI. Therapeutic approaches to increase neuronal expression of DPPI are therefore unlikely to be effective for treatment of LINCL.

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