Renee I Seinstra

University of Groningen; Groningen, Netherlands; University Medical Centre Groningen

OW477

Caenorhabditis elegans

OW478

Caenorhabditis elegans

OW479

Caenorhabditis elegans

Gungordu, Lale et al. (2021) International Worm Meeting "Modifiers of TDP-43 Toxicity"

Nollen, Ellen, Gungordu, Lale, Koopman, Mandy, Seinstra, Renee

[International Worm Meeting, 2021]

Protein toxicity is thought to underlie several, yet incurable, age-related neurodegenerative diseases, including Parkinson's disease and Amyotrophic Lateral Sclerosis (ALS). TDP-43 aggregation is the major pathological hallmark of ALS and present in 97% of all cases, suggesting that TDP-43 contributes to in the disease mechanism. How protein toxicity triggers cell-and physical dysfunction and leads to degeneration is still not understood. This project aims to find disease mechanisms and uncover targets to suppress ALS-related TDP-43 toxicity. For this aim, a combination of genetic- and phenotypic screens in a Caenorhabditis elegans model for disease are being used. We make use of a C.elegans strain with overexpressed human TDP-43, which shows several cellular- and behavioral ALS disease phenotypes, including age-related motor impairment is used as a model. We performed a genetic screen, which identified 22 mutant animals that show a suppression of this impairment. The strongest suppressor mutant, called MOTT-22 (Modifier of TDP-43 Toxicity 22), was selected for further experiments. We are currently verifying and characterizing a candidate gene that may be responsible for the suppression of motor impairment in MOTT-22. After finding a candidate gene for MOTT-22, gene functions in the cell will be studied to find new mechanisms involved in protein toxicity.

Sin, Olga et al. (2015) International Worm Meeting "Identification of MOAG-2/LIR-3 as a regulator of protein aggregation."

Guryev, Victor, Reinke, Valerie, Sin, Olga, Willinge Prins, Romeo, Wang, Hai Hui, Martineau, Celine, Mata Cabana, Alejandro, Seinstra, Renee, Nollen, Ellen, Kudron, Michelle, de Jong, Tristan

[International Worm Meeting, 2015]

Aging-related protein aggregation is one of the hallmarks of neurodegenerative disorders such as Alzheimer, Parkinson and polyglutamine diseases. The cellular processes that drive protein aggregation in these diseases have remained largely unknown. Using a genetic screen in a C. elegans model for polyglutamine aggregation, we here identified modifier of aggregation 2 (moag-2). Mutation or partial deletion in this gene decreased the number of aggregates in our model. Additionally, moag-2/lir-3 mutants reduce the amount of SDS-resistant aggregates without changing total polyglutamine expression levels. We discovered that the causative gene of moag-2 is lir-3. moag-2/lir-3 encodes a protein with a predicted nuclear localization signal and two non-canonical C2H2 domains, which are homologous to the transcription factor for RNA polymerase III. The molecular function of MOAG-2/LIR-3 is unknown. Chromatin immunoprecipitation followed by sequencing data revealed that MOAG-2/LIR-3 is preferentially bound to promoter regions of non-coding RNA, namely tRNAs and snoRNAs. The consensus DNA sequence to which MOAG-2/LIR-3 is bound to corresponds to Box A and Box B motifs, which are recognized by the RNA Polymerase III machinery to initiate tRNA and snoRNA transcription. In fact, MOAG-2/LIR-3 is positioned in the same binding positions as the RNA Pol III complex, further suggesting a role for LIR-3 in non-coding RNA transcription. We are currently performing total RNA sequencing to reveal whether the aggregation phenotype displayed by the MOAG-2/LIR-3 mutants can be due to imbalanced RNA metabolism. By unraveling the role of moag-2/lir-3 we hope to get insight into how cells cope with aggregation-prone proteins.