Biology subjects

De Decker, M.

Publications and source records attributed to De Decker, M..

3 recordsLinked to original sources

bioRxiv2022

C21orf2 mutations found in ALS disrupt primary cilia function

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects 1 in 400 people. Almost 40 genes have been associated with ALS, currently explaining about 15% of the ALS risk. These genes tend to cluster in certain disease pathways such as protein quality control, RNA metabolism and axonal function. Despite these advances, adequate treatments for ALS patients are still missing. In this study, we investigate the role of a newly discovered ALS gene, C21orf2, in ALS pathology. We show that C21orf2 is localized to the basal body of the primary cilium and plays an important role in ciliogenesis in vitro and in vivo. Knock down of C21orf2 also lowers cilia frequency and length in human iPSC-derived spinal motor neurons (sMNs). Furthermore, we show that intraflagellar transport is impaired, causing primary cilia to fail in transducing extracellular signals essential in the sonic hedgehog pathway. ALS-associated mutations in C21orf2 lead to loss of binding to centrosomal proteins, loss of proper localization at the basal body and hereby prevent C21orf2 from carrying out its normal function in cilia by loss-of-function. Finally, we confirm that sMNs derived from iPSCs from ALS patients with C21orf2 mutations display similar cilia dysfunction and have disturbed sonic hedgehog signaling. Collectively, our data reveal impaired cilia homeostasis as a novel disease mechanism at play in ALS, opening new avenues for further research.

neuroscience↗

bioRxiv2020

Hydration-dependent phase separation of a prion-like protein regulates seed germination during water stress.

Many organisms evolved strategies to survive and thrive under extreme desiccation. Plant seeds protect dehydrated embryos from a variety of stressors and can even lay dormant for millennia. While hydration is the key trigger that reactivates metabolism and kick-starts germination, the exact mechanism by which the embryo senses water remains unresolved. We identified an uncharacterized Arabidopsis thaliana prion-like protein we named FLOE1, which phase separates upon hydration and allows the embryo to sense water stress. We demonstrate that the biophysical states of FLOE1 condensates modulate its biological function in vivo in suppressing seed germination under unfavorable environments. We also find intragenic, intraspecific, and interspecific natural variations in phase separation propensity of FLOE1 homologs. These findings demonstrate a physiological role of phase separation in a multicellular organism and have direct implications for plant ecology and agriculture, especially the design of drought resistant crops, in the face of climate change.

cell biology↗

bioRxiv2019

C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility

Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How this mutation leads to these neurodegenerative diseases remains unclear. Here, we use human induced pluripotent stem cell-derived motor neurons to show that C9orf72 repeat expansions impair microtubule-based transport of mitochondria, a process critical for maintenance of neuronal function. Cargo transport defects are recapitulated by treating healthy neurons with the arginine-rich dipeptide repeat proteins (DPRs) that are produced by the hexanucleotide repeat expansions. Single-molecule imaging shows that these DPRs perturb motility of purified kinesin-1 and cytoplasmic dynein-1 motors along microtubules in vitro. Additional in vitro and in vivo data indicate that the DPRs impair transport by interacting with both microtubules and the motor complexes. We also show that kinesin-1 is enriched in DPR inclusions in patient brains and that increasing the level of this motor strongly suppresses the toxic effects of arginine-rich DPR expression in a Drosophila model. Collectively, our study implicates an inhibitory interaction of arginine-rich DPRs with the axonal transport machinery in C9orf72-associated ALS/FTD and thereby points to novel potential therapeutic strategies.

neuroscience↗