Driscoll, B. | bioRxiv Science

bioRxiv2025

Acyl-coA binding protein AcbdA regulates peroxisome hitchhiking on early endosomes

Motor-driven transport on microtubules is critical for distributing organelles throughout the cell. Most commonly, organelle movement is mediated by cargo adaptors, proteins on the surface of an organelle that directly recruit microtubule-based motors. An alternative mechanism called hitchhiking was recently discovered: some organelles move, not by recruiting the motors directly, but instead by using membrane contact sites to attach to motor-driven vesicles and hitchhike along microtubules. Organelle hitchhiking is observed across fungi and animals. In filamentous fungi, nearly all peroxisomes move by hitchhiking on early endosomes (EEs). In the fungus Aspergillus nidulans, EE-associated linker proteins PxdA and DipA are critical for establishing EE-peroxisome membrane contact sites required for peroxisome movement. How peroxisomes recognize this subset of EEs and what peroxisome-membrane proteins exist that can interact with EEs is not known. Here, we undertook a forward mutagenesis screen to identify such proteins. We discovered an acyl-coA binding (ACB) domain-containing protein AcbdA/AN1062 that localizes to peroxisomes via its tail-anchored transmembrane domain (TMD). Deleting the AcbdA gene or only its N-terminal ACB domain perturbs the movement and distribution of peroxisomes. Importantly, AcbdA is not required for the movement of EEs or for the recruitment of PxdA and DipA on EEs. Fatty acid (FA)-induced increases in peroxisome movement require AcbdA, suggesting that peroxisome hitchhiking on EEs is coupled to FA metabolism. Mutating a conserved FFAT motif, predicted to interact with the endoplasmic reticulum (ER), has no effect on peroxisome movement. Taken together, our data indicate that AcbdA is a peroxisome-membrane protein required to tether peroxisomes to EEs during hitchhiking. AcbdAs involvement in peroxisome-EE contact site formation represents a divergence from known functions of Acbd4/5 proteins and adds layers to our understanding of the functionality of the Acbd4/5 family of proteins.

cell biology↗

bioRxiv2024

Hippocampal ripples mediate motor learning during brief rest breaks in humans

Critical aspects of motor learning and memory happen offline, during both wake and sleep. When healthy young people learn a motor sequence task, most of their performance improvement happens not while typing, but offline, during interleaved rest breaks. In contrast, the performance of patients with dense amnesia due to hippocampal damage actually gets worse over the rest breaks and improves while typing. These findings indicate that an intact hippocampus is necessary for offline motor learning during wake, but do not specify its mechanism. Here, we studied epilepsy patients (n=17) undergoing direct intracranial EEG monitoring of the hippocampus as they learned the same motor sequence task. Like healthy young people, they showed greater speed gains across rest breaks than while typing. They also showed higher hippocampal ripple rates during these rest breaks that predicted offline gains in speed. This suggests that motor learning during brief rest breaks during wake is mediated by hippocampal ripples. These results expand our understanding of the role of hippocampal ripples beyond declarative memory to include enhancing motor procedural memory. Significance StatementIn patients with epilepsy undergoing direct intracranial EEG monitoring of the hippocampus, we found a higher rate of ripples during the brief rest breaks of a motor sequence task than during task execution. These offline hippocampal ripples predicted the amount of performance improvement over the break. We conclude that the hippocampus contributes to motor learning during brief rest breaks, and propose that this offline learning is mediated by ripples.

neuroscience↗