TY  - INPR
A1  - Pereira, Marisa
A1  - Ribeiro, Diana Roberta
A1  - Berg, Maximilian
A1  - Tsai, Andy Po-Yi
A1  - Nho, Kwangsik
A1  - Kaiser, Stefanie
A1  - Moutinho, Miguel
A1  - Soares, Ana Raquel
T1  - Amyloid pathology reduces ELP3 expression and tRNA modifications leading to impaired proteostasis in Alzheimer’s disease models
T2  - bioRxiv
N2  - Alzheimer’s Disease (AD) is a progressive and irreversible neurodegenerative disorder, characterized by the accumulation of abeta-amyloid aggregates, which triggers tau hyperphosphorylation and neuronal loss. While the precise mechanisms underlying neurodegeneration in AD are not entirely understood, it is known that loss of proteostasis is implicated in this process. Maintaining neuronal proteostasis requires proper transfer RNA (tRNA) modifications, which are crucial for optimal translation. However, research into tRNA epitranscriptome in AD is limited, and it is not yet clear how alterations in tRNA modifying enzymes and tRNA modifications might contribute to disease progression. Here, we report that expression of the tRNA modifying enzyme ELP3 is reduced in the brain of AD patients and amyloid AD mouse models, suggesting ELP3 is implicated in proteostasis dysregulation observed in AD. To investigate the role of ELP3 specifically in neuronal proteostasis impairments in the context of amyloid pathology, we analyzed SH-SY5Y neuronal cells carrying the amyloidogenic Swedish familial AD mutation in the APP gene (SH-SWE) or the wild-type gene (SH-WT). Similarly to the amyloid mouse models, SH-SWE exhibited reduced levels of ELP3 which was associated with tRNA hypomodifications and reduced abundance, as well as proteostasis impairments. Furthermore, the knock-down of ELP3 in SH-WT recapitulated the proteostasis impairments observed in SH-SWE cells. Importantly, the correction of tRNA deficits due to ELP3 reduction rescued and reverted proteostasis impairments of SH-SWE and SH-WT knock-down for ELP3, respectively. Additionally, SH-WT exposed to the secretome of SH-SWE or synthetic amyloid aggregates recapitulate the SH-SWE phenotype, characterized by reduced ELP3 expression, tRNA hypomodification and increased protein aggregation. Taken together, our data suggest that amyloid pathology dysregulates neuronal proteostasis through the reduction of ELP3 and tRNA modifications. This study highlights the modulation of tRNA modifications as a potential therapeutic avenue to restore neuronal proteostasis in AD and preserve neuronal function.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73989
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-739898
IS  - 2023.05.02.538928
ER  -