Parkinson’s disease is the second most common age-related neurodegenerative disorder characterized
by the formation of cellular inclusions inside neurons that predominantly consist of misfolded α-
synuclein (α-syn), leading to neuronal dysfunction. The clearance of α-syn aggregates by microglia, the
brain resident cells of the innate immune system, has emerged as particularly critical for the progression
of PD, as microglia have been shown to scavenge extracellular α-syn with the highest capacity among
all brain cells. Here, we report a novel mechanism of neuron-microglia communication through the
formation of tunneling nanotube (TNT)-like structures, which allow the extraction of fibrillar α-syn
aggregates from neurons into microglia. In turn, microglia donate their healthy mitochondria to
burdened neurons to maintain neuronal health thereby normalizing α-syn-induced intraneuronal levels
of radical oxygen species and aggregate-induced changes in the neuronal transcriptome. Compromising
mitochondrial function by treatment of microglia with the electron transport chain blocker Antimycin
A prior to the formation of TNT-like connections completely blocks these neuroprotective effects.
Likewise, α-syn-suppressed neuronal activity is rescued by co-incubation with microglia and formation
of TNTs. Aggregate transfer from neurons to microglia through TNT-like connections was reduced in
LRRK2 G2019S mutant microglia, suggesting that an impairment of the observed mechanism may
partly account for the pathology associated with this gene variant in Parkinson’s disease. With this, we
describe for the first time a novel rescue mechanism by which microglia actively clear neurons from
misfolded protein aggregates. Failure of this mechanism will be crucial to the disease progression and
have significant consequences for the outcome of the cells.