in-vivo-single-molecule-tracking-at-drosophila-presynaptic-motor

<em>In Vivo</em> Single-Molecule Tracking at the Drosophila Presynaptic Motor Nerve Terminal

An increasing number of super-resolution microscopy techniques are helping to uncover the mechanisms that govern the nanoscale cellular world. ...

Leuven Institute for Neurodegenerative Disease (LIND)

PINK1 is mutated in Parkinson's disease (PD), and mutations cause mitochondrial defects that include inefficient electron transport between complex I and ubiquinone. Neurodegeneration is also connected to changes in lipid homeostasis, but how these are related to PINK1-induced mitochondrial dysfunction is unknown. Based on an unbiased genetic screen, we found that partial genetic and pharmacological inhibition of fatty acid synthase (FASN) suppresses toxicity induced by PINK1 deficiency in flies, mouse cells, patient-derived fibroblasts, and induced pluripotent stem cell-derived dopaminergic neurons. Lower FASN activity in PINK1 mutants decreases palmitate levels and increases the levels of cardiolipin (CL), a mitochondrial inner membrane-specific lipid. Direct supplementation of CL to isolated mitochondria not only rescues the PINK1-induced complex I defects but also rescues the inefficient electron transfer between complex I and ubiquinone in specific mutants. Our data indicate that genetic or pharmacologic inhibition of FASN to increase CL levels bypasses the enzymatic defects at complex I in a PD model.

Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency.

Neurons are thought to primarily rely on glucose to fuel mitochondrial metabolism. In this issue, Divakaruni et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201612067) show that neurons are also happy to use glutamate. When neurons use this neurotransmitter, its concentration drops, thus protecting against glutamate-induced excitotoxic stress.

Neurons eat glutamate to stay alive.

α-Synuclein resides in Lewy bodies in Parkinson's disease. Ordonez et al. (2017) now show that α-syn disrupts the actin network, causing Drp1-dependent mitochondrial fission defects. This is similar to defects induced by the PD risk factor Tau, suggesting converging pathways in neurodegeneration.

Patrik Verstreken

VIB Centre for Brain and Disease Research,
KU Leuven Department of Neurosciences,
VIB Centre for Brain and Disease Research, KU Leuven Department of Neurosciences

Leuven Institute for Neurodegenerative Disease (LIND)

In Vivo Single-Molecule Tracking at the Drosophila Presynaptic Motor Nerve Terminal

Patrik Verstreken

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}VIB Centre for Brain and Disease Research,KU Leuven Department of Neurosciences,VIB Centre for Brain and Disease Research, KU Leuven Department of Neurosciences

Leuven Institute for Neurodegenerative Disease (LIND)

In Vivo Single-Molecule Tracking at the Drosophila Presynaptic Motor Nerve Terminal

VIB Centre for Brain and Disease Research,
KU Leuven Department of Neurosciences,
VIB Centre for Brain and Disease Research, KU Leuven Department of Neurosciences