Year: 2012
Type: dissertation
Abstract: 656-4 (pdf)Neuronal ceroid lipofuscinoses (NCLs) are a collective group of recessively inherited severe neurodegenerative diseases of childhood.NCLs are characterised by progressive, selective neuronal death and lysosomal accumulation of autofluorescent storage material, ceroid lipofuscin, which lead to variable but progressive symptoms, including epileptic seizures, blindness, motor and mental deterioration, and premature death.Genetics of NCLs is well described, and several causative genes have been identified.However, due to the poor knowledge on the functions of the proteins primarily defective in NCLs, the intracellular changes critical to the pathogenesis of NCLs are not known.In this thesis study, NCL was studied in terms of its classic juvenile onset form, juvenile CLN3 disease, caused by mutations in a CLN3 gene.CLN3 encodes primarily late endosome/lysosome-localised Molecular Interactions of Neuronal Ceroid Lipofuscinosis Protein CLN3processes.Subsequently, CLN3 was found to interact with motor proteins, dyneindynactin and kinesin-2-dynactin, most likely through its direct interactions with Rab7 GTPase and its effector Rab7-interacting lysosomal protein (RILP).Previously, it has been reported that together with oxysterol-binding protein-related protein 1L (ORP1L), Rab7 and RILP facilitate the recruitment of dynein-dynactin motor protein to late endosomal/lysosomal membranes and thus, enhance the minus end-directed movement of late endosomes and lysosomes.Rab7-containing effector complex has also been suggested to regulate kinesin-dependent movement of organelles, and thus, may link CLN3 to these functions as well.Interestingly, several observations indicated that the late endosomal/lysosomal membrane trafficking is affected in CLN3 deficiency.First, disease-associated CLN3 mutants were found to interact differently with Rab7 and RILP proteins.Second, late endosomes and lysosomes in CLN3 mutant-expressing cells were observed to be abnormally clustered to the perinuclear area.Third, functional GTP/GDP cycle of Rab7 was found to be affected in CLN3 deficiency.Fourth, CLN3-deficient cells exhibited delays in the late endosomal transport of endocytosed cargo, and kinesin-dependent movement of late endosomes/lysosomes.These results suggested that Rab7-guided microtubular motor protein functions in neurons, such as axonal retrograde trafficking of neurotrophins, neurite outgrowth and maturation, and transportation of neuronal autophagic vesicles could also be dysregulated in juvenile CLN3 disease.This thesis work has provided important novel data on the functions of CLN3 and the primary intracellular defects possibly resulting in CLN3 disease.This study also contributes to the determination of the pathogenesis of other NCLs and general processes of neurodegeneration.
Source: Työväentutkimus Vuosikirja
Author: Kristiina Uusi-Rauva
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2177094048