The roles of Drosophila ubiquilin in neurological disorders

神経疾患におけるショウジョウバエユビクリンの役割

2018-09-25

2018-09-25

The RNA processing and protein homeostasis are a critical mechanism in metabolically active cells such as neurons. The perturbation of either of them leads to neurological disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Drosophila is emerging as a useful model for simplifying our understanding on the pathological mechanisms caused by both processes. My recent findings demonstrated that the aberration of both processes can induce the neurotoxicity in Drosophila. I revealed that the human FUS (hFUS), one of the important RNA binding protein was able to induce an aberrant eye morphology with loss of pigmentation in Drosophila, producing an excessive soluble hFUS partition and inducing some autophagic markers highlighting the close link between RNA processing and protein homeostasis. Moreover, the depletion of Drosophila Ubiquilin (dUbqn), a single ubiquilin homolog that shows high similarity to human ubiquilins perturbed brain protein homeostasis, learning/memory and locomotive abilities underpinning an important role of dUbqn in deciding the fate of ubiquitinated and misfolded proteins to be degraded by the ubiquitin-proteasome system (UPS) and/or autophagy. Interestingly, the depletion of dUbqn also markedly affected the expression and sub-cellular localization of TBPH, an ortholog of human TAR DNA-binding protein 43 (TDP43) that was recognized as a major component of the ubiquitin pathology, resulting a cytoplasmic ubiquitin-positive (Ub+) TBPH pathology. Although, dUbqn widely manages the turnover of a large number of proteins, I herein showed that an augmented soluble cytoplasmic Ub+TBPH was as a crucial source of neurotoxicity following the depletion of dUbqn. I demonstrated that dUbqn knockdown-related neurotoxicity could be rescued by either restoring the proteostasis machinery or reducing the expression of TBPH. These novel findings extend our knowledge on the pathomechanism of proteostasis and RNA binding protein impairment and may contribute to the identification of new therapeutics for ALS-FTD and other neurological-related disorders.

博士（学術）

京都工芸繊維大学

14303甲第889号

http://hdl.handle.net/10212/2491

eng

ETD

3

Thesis or Dissertation

Thesis