Reconstitution of the Human Nigro-striatal Pathway on-a-Chip Reveals OPA1-Dependent Mitochondrial Defects and Loss of Dopaminergic Synapses

Angelo Iannielli, Giovanni Stefano Ugolini, Chiara Cordiglieri, Simone Bido, Alicia Rubio, Gaia Colasante, Marco Valtorta, Tommaso Cabassi, Marco Rasponi, Vania Broccoli

Research output: Contribution to journalArticlepeer-review

Abstract

Stem cell-derived neurons are generally obtained in mass cultures that lack both spatial organization and any meaningful connectivity. We implement a microfluidic system for long-term culture of human neurons with patterned projections and synaptic terminals. Co-culture of human midbrain dopaminergic and striatal medium spiny neurons on the microchip establishes an orchestrated nigro-striatal circuitry with functional dopaminergic synapses. We use this platform to dissect the mitochondrial dysfunctions associated with a genetic form of Parkinson's disease (PD) with OPA1 mutations. Remarkably, we find that axons of OPA1 mutant dopaminergic neurons exhibit a significant reduction of mitochondrial mass. This defect causes a significant loss of dopaminergic synapses, which worsens in long-term cultures. Therefore, PD-associated depletion of mitochondria at synapses might precede loss of neuronal connectivity and neurodegeneration. In vitro reconstitution of human circuitries by microfluidic technology offers a powerful system to study brain networks by establishing ordered neuronal compartments and correct synapse identity.

Original languageEnglish
Pages (from-to)4646-4656.e4
JournalCell Reports
Volume29
Issue number13
DOIs
Publication statusPublished - Dec 24 2019

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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