Biology subjects

Seinstra, R. I.

Publications and source records attributed to Seinstra, R. I..

4 recordsLinked to original sources

bioRxiv2025

Condensate-Driven Triglyceride Depletion Links α-Synuclein to Mitochondrial Dysfunction

Inclusions of -Synuclein (Syn) characterize multiple age-related neurodegenerative diseases, including Parkinsons disease (PD) and Multiple System Atrophy (MSA). While interactions between Syn and lipids are known to contribute to Syn pathobiology, the precise cellular mechanisms that link lipids to Syn toxicity have yet to be elucidated. Through lipidomic profiling of Caenorhabditis elegans, we found that Syn progressively alters lipid metabolism in aging worms. Syn strongly reduces overall content of triacylglycerols (TAG) and disrupts the structure of lipid droplets (LD). These pathological changes depend on Syns properties to condensate and form inclusions. Apart from lowering TAG levels, Syn also increases the proportion of long-chain unsaturated fatty acids (LCUFAs). Consequently, genetic inhibition of LCUFA biosynthesis alleviates Syn-induced loss of C. elegans motility. Strikingly, bypassing lipid metabolic defects by supplementing Medium Chain Fatty Acids (MCFAs) restores the Syn-impaired mitochondrial response and rescues motility. These results link Syn condensation to impaired TAG metabolism, which reduces mitochondrial function and enhances overall toxicity. Together with the finding that plasma TAGs are lowered in Parkinson patient cohorts, these results suggest that restoring TAG metabolism could alleviate Syn-induced toxicity in Parkinsons and other age-related synucleinopathies.

cell biology↗

bioRxiv2023

Rebalancing the motor circuit restores movement in a Caenorhabditis elegans model for TDP-43-toxicity

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are caused by the abnormal accumulation of TAR DNA-binding protein 43 (TDP-43) in the cytoplasm of neurons. How TDP-43 accumulation leads to disease symptoms is not well-characterized. Here, we use a C. elegans model for TDP-43-induced toxicity to identify the biological mechanisms that lead to disease-related phenotypes. By applying deep behavioral phenotyping, we established a phenotypic fingerprint of TDP-43 worms. This fingerprint was compared to that of 294 C. elegans mutants, in which genes were mutated that are important for nervous system and muscle functioning. By using a computational clustering approach, we found that the release of acetylcholine and GABA was the primary defect in TDP-43 worms. We then functionally dissected the neuromuscular circuit to show that GABA transmission was more severely diminished compared to acetylcholine. Whereas the loss of GABA transmission was caused by a profound loss of GABA synapses, acetylcholine neurons appeared to be functionally silenced. Enhancing functional output of repressed acetylcholine neurons at the level of G-protein coupled receptors or through optogenetic stimulation restored neurotransmission, but inefficiently rescued locomotion. Surprisingly, rebalancing the excitatory and inhibitory input by simultaneous stimulation of GABA and acetylcholine input into muscles not only synergized the effects of boosting individual neurotransmitter systems, but instantaneously improved movement. Our results suggest that interventions accounting for the altered connectome may be more efficient in restoring motor function than those solely focusing on diseased neuron populations.

cell biology↗

bioRxiv2019

Deep behavioural phenotyping reveals divergent trajectories of ageing and quantifies health state in C. elegans

Neurodegenerative diseases may be the cause or the consequence of an acceleration of physiological ageing. Evidence for this concept is lacking due to practical limitations of human studies. Here, we compared the processes of physiological and pathological ageing of individual C. elegans over their lifespan. Using multi-parametric phenotyping, trajectories of ageing can be defined within a phenotypic landscape made of a large set of phenotypical features. Rather than an acceleration of ageing, a model for synucleinopathy showed a divergent trajectory of ageing. The pathological progression in individual animals can be predicted from early phenotypes with high accuracy. Despite of similar lifespans, disease-model worms display an early onset of decline in their phenotypic range of ability. This loss of flexibility provides an index of health valid for physiological and pathological contexts. Finally, we demonstrate the power of multi-parametric dataset to describe ageing, to quantify health and to predict specific health risks.

systems biology↗

bioRxiv2018

Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging

Aging is a major risk factor for human morbidity and mortality. Thus, the identification of compounds that defer aging, also known as geroprotectors, could greatly improve our health and promote a longer life. Here we screened for geroprotectors, employing the power of human transcriptomics to predict biological age. We used age-stratified human tissue transcriptomes to generate machine-learning-based classifiers capable of distinguishing transcriptomes from young versus old individuals. Then we applied these classifiers to transcriptomes induced by 1300 different compounds in human cell lines and ranked these compounds by their ability to induce a youthful transcriptional state. Besides known geroprotectors, several new candidate compounds emerged from this ranking. Testing these in the model organism C. elegans, we identified two Hsp90 inhibitors, Monorden and Tanespimycin, which substantially extended the animals lifespan and improved their health. Hsp90 inhibition specifically induces the expression of heat shock proteins, known to improve protein homeostasis. Consistently, Monorden treatment improved the survival of C. elegans under proteotoxic stress, and its lifespan benefits were fully dependent on the master regulator of the cytosolic unfolded protein response, the transcription factor HSF-1. Taken together, we present an innovative transcriptomics-based screening approach to discover aging-preventive compounds and highlight Hsp90 inhibitors as powerful geroprotectors that could be of great value, to target the aging process in humans.

cell biology↗