S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Master's Degree_의과학과)
Generation & Characterization of NPC1-deficient or CLN3-deficient neuronal cell lines
NPC1 유전자 결손 신경세포주와 CLN3 유전자 결손 신경세포주 구축 및 성질 분석
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (석사)-- 서울대학교 대학원 : 의과대학 의과학과, 2018. 8. 이승재.
- Lysosomal storage diseases (LSDs) are metabolic diseases that result from lysosomal failure. LSDs are characterized by the abnormal deposition of the un-degraded materials in lysosomes. Many studies demonstrated that over 50% of LSDs are accompanied by the neurological symptoms. Furthermore, some LSD-linked genes such as GBA1, GRN, NPC1 are known to be associated with pathogenesis of neurodegenerative diseases. Although, increasing evidence suggested that LSDs and neurodegenerative diseases share many common features, the roles of LSD-linked genes in the pathogenic mechanism of neurodegenerative disorders remain elusive. Niemann-Pick type C (NPC) disease is caused by mutations in either the NPC1 or NPC2 genes. Dysfunction of NPC1 protein has been shown to affect intracellular cholesterol metabolism inhibiting cholesterol efflux from lysosomes. Pathological studies on NPC1 patients reported a significant increase in tau phosphorylation and development of neurofibrillary tangles (NFTs), which are major pathological hallmarks in Alzheimers disease (AD). On the other hand, some studies on NPC1 patients reported aberrant phosphorylation of α-synuclein in the substantia nigra and the occurrence of Lewy bodies in the cerebral cortex and brainstem. A clinical study showed that three adults who were heterozygous carriers of mutations in the NPC1 had the parkinsonian syndrome. Also, some juvenile neuronal ceroid lipofuscinosis (NCL) patients with CLN3 mutation showed that some evidences for parkinsonian symptoms, decreased striatal dopamine transporter and loss of dopaminergic neurons in substantia nigra pars compacta. On that basis, I hypothesized that dysfunctions of specific LSD-linked gene could trigger the specific neurodegenerative disorder by inducing alterations in the neurodegenerative disorder-linked protein metabolisms. Herein, I generated NPC1-deficient or CLN3-deficient SH-SY5Y cell lines. Depletions of NPC1 or CLN3 reduced the lysosomal activity and resulted in the accumulation of lysosomes and lysosomal substrates. And, I found the increase in the deposition of α-synuclein and total tau level in NPC1-deficient cells, whereas only α-synuclein aggregates was increased in CLN3-deficient cells. These results suggested that the deficiency of specific LSD-linked gene could trigger the lysosomal defects which result in different effect on neurodegenerative disease-linked protein metabolism. NPC1-deficient or CLN3-deficient cell models can be a useful tool to investigate the roles of lysosomal malfunction induced by LSD-linked gene deficiency in the pathogenesis of neurodegenerative diseases.
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