Complex I loss in dopamine neurons

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Patricia González-Rodríguez, D. James Surmeier (senior author) and colleagues (Northwestern University, with José López-Barneo's group in Seville and Michael Kaplitt's at Weill Cornell). Nature 599:650–656, online 3 November 2021. The Europe PMC record shows NIH funding; I did not read the funding statement.

What happened

Complex I, the first step in the cell's energy chain, was found reduced in Parkinson's brains (landmark 11), but it was unclear whether this causes disease. The team deleted Ndufs2, an essential part of complex I, only in dopamine neurons, using a two-step genetic method. The paper title is "Disruption of mitochondrial complex I induces progressive parkinsonism". Per the abstract: the neurons survived by shifting to a Warburg-like metabolism (energy from sugar breakdown rather than the mitochondria), but progressively lost their dopamine-making identity, first in the nigrostriatal axons. Early on the mice had motor-learning and fine-movement deficits but not clear levodopa-responsive parkinsonism, which appeared only after dopamine release inside the substantia nigra itself was lost later. The authors conclude that complex I failure alone can cause progressive, human-like parkinsonism, and that loss of nigral dopamine release contributes to the movement problems.

Why it moved us toward a cure

It shows that an energy defect inside the vulnerable neurons can on its own produce the disease pattern, and gives a progressive mouse model to test energy-rescue drugs.

Outcome

Advanced. A mouse with a total gene deletion is much harsher than the partial loss in patients. An author correction was published (Nature 2022;603:E1, DOI 10.1038/s41586-021-04382-6); it replaced two bottom-left panels of Extended Data Fig. 8b that duplicated open-field panels from Fig. 4d (read at nature.com, checked 23 Oct 2026). Several commentaries accompanied the paper (Nature, Nat Neurosci, Mov Disord).

Sources

• González-Rodríguez et al., Nature 2021, DOI 10.1038/s41586-021-04059-0, PMID 34732887
• Author correction, Nature 2022;603:E1, DOI 10.1038/s41586-021-04382-6 (replaced two duplicated image panels; no data change stated)
• Full text read at PMC9189968.
• Not yet verified: the exact ages at which each deficit appeared; any non-motor detail.