Genetika frontotemporalnih demencija

master's thesis

• Title (english): Genetic Basis of Frontotemporal Dementia
• Author: Ivna Tomaš
• Mentor: Marina Boban (mentor)
• Committee member: Srđana Telarović (predsjednik povjerenstva)
• Committee member: Mario Habek (član povjerenstva)
• Committee member: Marina Boban (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Neurology); Zagreb
• Defense date and country: 2024-07-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Neurology

Abstract

Frontotemporalna demencija (FTD) je progresivni neurodegenerativni poremećaj koji prvenstveno zahvaća frontalne i temporalne režnjeve mozga dovodeći do značajnih promjena u osobnosti, ponašanju i govoru. To je drugi najčešći uzrok demencije s ranim početkom koji tipično pogađa osobe između 45. i 65. godine života. Etiologija FTD-a je vrlo heterogena, a znatan dio slučajeva pripisuje se genetskim mutacijama (30-50%). Tri gena najčešće povezana s obiteljskim FTD-om su MAPT, GRN i C9orf72. Mutacije u genu MAPT dovode do proizvodnje abnormalnih tau proteina, što rezultira formiranjem neurofibrilarnih snopića koji ometaju normalnu funkciju neurona. Mutacije gena GRN modificiraju koncentraciju i funkciju progranulina, proteina ključnog za preživljenje neurona i regulaciju upale. GRN i C9orf72 mutacije dovode do različitih neuropatoloških obilježja, uključujući TDP-43 proteinopatije. Heksanukleotidne ekspanzije u genu C9orf72 najčešći su genetski uzrok FTD-a, a povezane su i s amiotrofičnom lateralnom sklerozom (ALS). Nedavnim napretkom genetskih istraživanja identificirani su brojni geni povezani s FTD-om. Mutacije dovode do nastanka FTD-a putem različitih patogenih mehanizama, naglašavajući genetsku složenost bolesti. Razumijevanje genetske pozadine FTD-a omogućava razvoj personalizirane medicine, s ciljem prilagodbe farmakoterapije specifičnom genetskom profilu pojedinca. Brojne potencijalne terapijske strategije još su u ranoj kliničkoj fazi istraživanja. Genetsko savjetovanje i testiranje također postaju integralni dio identificiranja rizičnih osoba. Zaključno, genetska pozadina frontotemporalne demencije je složena te uključuje brojne gene i patogenetske mehanizme. Nastavak istraživanja genetskih uzroka i molekularnih puteva FTD-a ključan je za razvoj ciljane terapije koja bi u budućnosti mogla modificirati tijek bolesti i poboljšati ishode liječenja oboljelih.

Abstract (english)

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that primarily affects the frontal and temporal lobes of the brain, leading to significant changes in personality, behaviour, and speech. It is the second most common cause of early-onset dementia, typically affecting individuals between the ages of 45 and 65. The aetiology of FTD is highly heterogeneous, with a substantial proportion of cases attributed to genetic mutations (30-50%). The three most commonly implicated genes in familial FTD are MAPT, GRN, and C9orf72. Mutations in the MAPT gene lead to the production of abnormal tau proteins, resulting in the formation of neurofibrillary tangles, which disrupt normal neuronal function. GRN gene mutations cause a reduction in progranulin levels, a protein crucial for neuronal survival and inflammation regulation. Both GRN and C9orf72 gene mutations lead to diverse neuropathological features, including TDP-43 proteinopathies. The hexanucleotide repeat expansion in the C9orf72 gene is the most frequent genetic cause of FTD and is also associated with amyotrophic lateral sclerosis (ALS). Recent advances in genetic research have identified additional genes associated with FTD. Each gene contributes to FTD via distinct pathogenic mechanisms, underscoring the genetic complexity of the disease. Understanding the genetic background of FTD can aid in the development of personalized medicine approaches. Efforts to develop gene therapies are underway, with many novel therapeutic strategies currently in early clinical stages. These developments hold promise for more effective treatments in the future. Genetic counselling and testing are also becoming integral parts of identifying at-risk individuals. In conclusion, the genetic background of frontotemporal dementia involves various genes and pathogenic mechanisms; continued research into FTD is essential for developing targeted therapies and improving outcomes for patients.

• Keywords: frontotemporalna demencija; frontotemporalna lobarna degeneracija; genetika; C9orf72 protein; tau protein; progranulin
• Keywords (english): frontotemporal dementia; frontotemporal lobar degeneration; genes; C9orf72 protein; tau protein; progranulin
• Language: croatian
• URN:NBN: urn:nbn:hr:105:250282
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-06-26 17:24:46