scholarly journals Mutational Analysis of the Defective Protease in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis, a Neurodegenerative Lysosomal Storage Disorder

1999 ◽  
Vol 64 (6) ◽  
pp. 1511-1523 ◽  
Author(s):  
David E. Sleat ◽  
Rosalie M. Gin ◽  
Istvan Sohar ◽  
Krystyna Wisniewski ◽  
Susan Sklower-Brooks ◽  
...  
Keyword(s):  
Lysosomal Storage Disorder ◽  
Mutational Analysis ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Storage Disorder

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.

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.

Sign in / Sign up

Export Citation Format

Share Document