Neuroglial transmitophagy and Parkinson's disease
Fecha
2020Resumen
Mitophagy is essential for the health of dopaminergic neurons because mitochondrial
damage is a keystone of Parkinson's disease. The aim of the present work was to study
the degradation of mitochondria in the degenerating dopaminergic synapse. Adult
Sprague–Dawley rats and YFP-Mito-DAn mice with fluorescent mitochondria in dopaminergic neurons were injected in the lateral ventricles with 6-hydroxydopamine, a
toxic that inhibits the mitochondrial chain of dopaminergic neurons and blockades the
axonal transport. Dopaminergic terminals closest to the lateral ventricle showed an
axonal fragmentation and an accumulation of damaged mitochondria in 2–9 μ saccular
structures (spheroids). Damaged mitochondria accumulated in spheroids initiated
(showing high Pink1, parkin, ubiquitin, p-S65-Ubi, AMBRA1, and BCL2L13 immunoreactivity and developing autophagosomes) but did not complete (mitochondria were not
polyubiquitinated, autophagosomes had no STX17, and no lysosomes were found in
spheroids) the mitophagy process. Then, spheroids were penetrated by astrocytic processes and DAergic mitochondria were transferred to astrocytes where they were
polyubiquitinated (UbiK63+) and linked to mature autophagosomes (STX17+) which
became autophagolysosomes (Lamp1/Lamp2 which co-localized with LC3). Present
data provide evidence that the mitophagy of degenerating dopaminergic terminals
starts in the dopaminergic spheroids and finishes in the surrounding astrocytes (spheroid-mediated transmitophagy). The neuron-astrocyte transmitophagy could be critical
for preventing the release of damaged mitochondria to the extracellular medium and
the neuro-inflammatory activity which characterizes Parkinson's disease.