التفاصيل البيبلوغرافية
| العنوان: |
CRISPR interference-based functional genetic interaction mapping in FTD/ALS and PD |
| المؤلفون: |
Humble, SW |
| المساهمون: |
Wade-Martins, R, Ryan, B, Ward, M, Talbot, K, Bassett, A |
| سنة النشر: |
2023 |
| المجموعة: |
Oxford University Research Archive (ORA) |
| مصطلحات موضوعية: |
Neurobiology, Genetics, CRISPR (Genetics), Lysosomes, Molecular neurobiology, Lysosomal storage diseases, Genetic engineering |
| الوصف: |
Parkinson’s disease (PD) and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTD/ALS) are progressive neurodegenerative diseases that are neuropathologically defined by the presence of protein aggregates and the loss of specific subsets of neurons. Both diseases are associated with variants in genes that are implicated in lysosome function and proteostasis. Therefore, it is likely that converging disease pathways exist across these subsets of neurodegeneration, and the interrogation of these pathways can be used both to enhance our understanding of these disorders and lead to innovative therapeutic interventions. Utilizing a modified i3Neuron platform to facilitate systematic single and pairwise knockdown (KD) of large panels of PD and FTD/ALS-associated genes through CRISPR interference (CRISPRi) to interrogate gene-gene interactions. My efforts focus on generating the first genetic interaction maps between the major genetic causes and risk factors of PD and FTD/ALS. Most notably, our interaction screen has identified several top gene-gene interaction candidates: TARDBP-TMEM106B, CLN8-NBR1, ATP13A2-CLN8, GRN-TMEM106B, and CTSL-GRN. TMEM106B was a component of multiple hits, and a recent study has demonstra- ted that it modifies TDP-43 pathology [1], while overexpression induces cell death and causes the cleavage of TDP-43 [2]. Additionally, it has been implicated as an interactor of GRN in the clinic [3, 4], and as a regulator of lysosomal function and acidification in mice [4, 5]. A remarkable trend was apparent across all interactions with TMEM106B, where the pH is significantly lower than the non-targeting comparison, indicating a postive overall effect on lysosomal function with knockdown. Strikingly, there is no significant phenotype between CTSL-GRN and non-targeting controls across DQ-BSA assays or the Magic Red assay, despite the severe deficits seen in GRN single KD. Lysosomal pH, however, is decreased significantly, which indicates a potential rescue across all assays. It is known that CTSL ... |
| نوع الوثيقة: |
thesis |
| اللغة: |
English |
| العلاقة: |
https://ora.ox.ac.uk/objects/uuid:f596e949-c34c-43ea-834b-ca1bbf20591aTest |
| الإتاحة: |
https://ora.ox.ac.uk/objects/uuid:f596e949-c34c-43ea-834b-ca1bbf20591aTest |
| حقوق: |
info:eu-repo/semantics/embargoedAccess |
| رقم الانضمام: |
edsbas.6E2FDA23 |
| قاعدة البيانات: |
BASE |
