Julia Fitzgerald

28 Oct 2026 15:00h

»The mitochondrial kinase PINK1 regulates cholesterol homeostasis affecting dopaminergic neuron functionality via the dopamine transporter«

Julia Fitzgerald

Hertie Institute for Clinical Brain Research

University of Tübingen

Location:

University Hospital

Goethe University

Seminarroom, IBCII, Bldg. 75

Abstract:

Cholesterol is a key lipid enriched in neuronal membranes and essential for signaling and synaptic transmission. An imbalance in cholesterol levels may affect synaptic plasticity and contribute to neurodegeneration. Here, we identify in human dopaminergic neurons a mechanism linking loss of function of the Parkinson’s disease (PD) gene PINK1 to altered cholesterol homeostasis. Loss of functional PINK1 impaired SCAP phosphorylation at Ser822 and Ser838, stabilizing SCAP and driving excess cholesterol biosynthesis. Cholesterol accumulated at the plasma membrane in flotillin-rich lipid rafts, causing reduced neurotransmitter uptake, altering the distribution of dopamine transporter (DAT) and neuronal firing activity. Restoring PINK1 expression normalized cholesterol biosynthesis and levels. Moreover, the cholesterol-lowering drugs simvastatin and β-cyclodextrin rescued DAT distribution and neurotransmitter defects.

These findings further highlight the cross-talk between mitochondria and lipid homeostasis in PD models and provide evidence for PINK1-induced specific vulnerability of the dopaminergic neurons that go beyond mitophagy. This work raises questions about the link between reduced mitochondrial quality control, autophagy, metabolism and the lysosome in context of their requirement for lipids and whether there is a potential biological trade-off that ultimately damages the dopaminergic system.