Molekularni mehanizmi neurodegeneracije u traumatskoj ozljedi mozga: uloga TAR DNA-vezujućeg proteina 43

Molecular mechanisms of neurodegeneration in traumatic brain injury: the role of TAR DNA-binding protein 43

Traumatska ozljeda mozga (engl. traumatic brain injury, TBI) jedan je od čimbenika rizika za razvoj neurodegenerativnih oboljenja poput Alzheimerove i Parkinsonove bolesti, te amiotrofične lateralne skleroze (ALS) i frontotemporalne lobarne degeneracije (FTLD). U ALS-u i FTLD-u glavnu komponentu citoplazmatskih inkluzija u degeneriranim neuronima čini TAR DNA-vezujući protein 43 (engl. TAR DNA-binding protein 43, TDP-43). Fiziološki je TDP-43 uglavnom smješten u jezgri, no istraživanja su pokazala da je njegova patološka funkcija moguće povezana s trajnim premještanjem iz jezgre u citosol. Uzroci razvoja TDP-43 proteinopatije još uvijek su nejasni, no poznato je da unutarstaničnu translokaciju TDP-43 mogu potaknuti aksotomija, stanični stres te mutacije gena ili prekomjerna ekspresija ovog proteina. TDP-43 proteinopatija zabilježena je i u osoba s TBI što je potvrđeno i u studijama u kojima su korišteni različiti eksperimentalni modeli traume mozga, ali još uvijek je nejasan točan mehanizam koji povezuje TDP-43 proteinopatiju i neurodegeneraciju nakon TBI. Moguće je objašnjenje patološkog utjecaja TDP-43 proteinopatije na neurone vezano uz aktivaciju upale, jednog od najvažnijih procesa sekundarne ozljede nakon TBI, što dosad nije bilo istraživano. Glavne hipoteze projekta su: 1. jednokratna umjerena TBI u miša uzrokuje TDP-43 proteinopatiju koja se može detektirati u različitim moždanim regijama i vrstama stanica središnjeg živčevlja, te 2. TBI u TDP-43 transgeničnog miša uzrokuje značajno jaču neuroupalu u odnosu na miševe divljeg tipa što je povezano s aktivacijom specifičnih signalnih puteva upale. U istraživanju će se koristiti model lateralne ozljeda mozga tlakom tekućine te će se u različitim vremenskim točkama nakon TBI analizirati izražaj TDP-43 u mišjem mozgu. Istraživat će se i upalni markeri te pratiti aktivacija signalnih puteva neuroupale. Rezultati ovog projekta trebali bi doprinijeti novim znanjima o ulozi TDP-43 u razvoju neurodegeracije nakon TBI.

Traumatic brain injury (TBI) is one of the risk factors for the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, and amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). In ALS and FTLD, the major component of cytoplasmic inclusions in degenerated neurons is TAR DNA-binding protein 43 (TDP-43). Physiologically, TDP-43 is mainly located in the nucleus, but studies have shown that its pathological function is associated with its permanent shift into the cytosol. Causes of TDP-43 proteinopathy development are still unclear, but it is well known that the intracellular TDP-43 translocation may be induced by axotomy, cellular stress as well as gene mutation or overexpression of this protein. TDP-43 proteinopathy was also observed in people with TBI, which was confirmed in studies using different TBI animal models. Still, the exact mechanism that links TDP-43 proteinopathy and neurodegeneration after TBI is unclear. A possible explanation of the effects of TDP-43 proteinopathy on neurons is related with the activation of inflammation, one of the most important secondary injury processes after TBI, but this has not been investigated so far. The main hypotheses are: 1. single moderate TBI in the mouse causes TDP-43 proteinopathy that can be detected in different brain regions and types of central nervous system cells, and 2. TBI in TDP-43 transgenic mice causes significantly stronger neuroinflammation compared to wild-type mice, which is due to the activation of some inflammation signaling pathways. In this study lateral fluid percussion brain injury model in the mouse will be used and the brain expression of TDP-43 will be analyzed at different post-injury time points. Inflammation markers and the activation of specific signaling pathways will also be investigated. The results of this project should contribute to new knowledge about the role of TDP-43 in the development of neurodegeneration after TBI.