Biology subjects

Pfau, M.

Publications and source records attributed to Pfau, M..

3 recordsLinked to original sources

bioRxiv2026

COQ8 chaperones coenzyme Q lipid intermediates through ATP-driven structural gating

Coenzyme Q biosynthesis requires the atypical kinase-like COQ8 proteins, whose ATPase activity streamlines the membrane-associated COQ metabolon, yet its molecular mechanism has remained unclear. Taking advantage of the tetrapod ancestral coenzyme Q biosynthetic machinery and liposomes mimicking the inner mitochondrial membrane, we show that COQ8A and COQ8B act as a streamlining factor for the coenzyme Q metabolon by engaging in loose protein-protein interactions and delivering insoluble biosynthetic intermediates. Structural bioinformatics and pathological-variant-driven mutagenesis reveal that coenzyme Q intermediates are recognized via their head-groups in a pocket whose access is gated by long-range conformational changes controlled by ATP hydrolysis. Finally, it is demonstrated that excess coenzyme Q suppresses binding of early-stage intermediates and thereby abolishes the streamlining effect of COQ8 on the metabolon. Together, these results support a model in which COQ8 functions as a biochemical coenzyme Q sensor that tunes coenzyme Q biosynthesis by coupling ATPase-driven intermediate chaperoning with feedback regulation by the final product. TeaserCOQ8 enhances coenzyme Q metabolic flux via ATP hydrolysis-driven chaperoning of biosynthetic intermediates.

biochemistry↗

bioRxiv2020

LRRK2 mutation alters behavioral, synaptic and non-synaptic adaptations to acute social stress

Parkinsons disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation LRRK2-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wildtype (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonic-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus, G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans.

neuroscience↗

bioRxiv2019

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have a wide variety of negative effects on patients, their families, and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, repeated domination of subordinate social targets is reinforcing. Here, we show that orexin neurons originating from the lateral hypothalamus activate a small population of GABAergic interneurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) to promote aggression and conditioned place preference (CPP) for aggression-paired contexts. Our study suggests that the orexin system is a potential target for the development of novel therapies aimed at reducing aggressive behaviors and provides the first functional evidence of a local inhibitory circuit within the LHb.

neuroscience↗