Mitochondrial DNA deletions in nigral 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

Andreas Bender, Doug Turnbull and colleagues at Newcastle University (UK), and Yevgenya Kraytsberg, Konstantin Khrapko and colleagues at Harvard Medical School, with neuropathologists Ann McKee, Changiz Geula and Neil Kowall. Both papers appeared in Nature Genetics, May 2006.

What happened

Mitochondria, the cell's power plants, carry their own small ring of DNA (mtDNA). Both teams measured, neuron by neuron, how much of it had large "deletions" (missing stretches that stop a mitochondrion working properly). Newcastle found that in nigral neurons from aged controls 43.3% ± 9.3% of mtDNA was deleted, versus 52.3% ± 9.3% in people with Parkinson's. The deletions were somatic (acquired in life), differed from cell to cell, and high levels went with loss of the respiratory enzyme cytochrome c oxidase (COX). The Harvard team used single-molecule PCR (the Alzforum report gives nine donors aged 33 to 102) and found a high proportion of aged nigral neurons with very high deletion levels. Deletions were clonal within each neuron (one deleted molecule had multiplied) and higher in COX-deficient neurons. Some neurons exceeded 60% deletions, a level often assumed to impair respiration. Deletions were far scarcer outside the substantia nigra.

Why it moved us toward a cure

It gave a concrete, tissue-specific explanation for why age is the strongest risk factor and why this brain region is vulnerable, following the earlier finding of a Complex I defect (landmark 11). It sits beside the gene-based mitochondrial story (landmark 15) and the mouse model that deletes a mitochondrial gene only in dopamine neurons (landmark 42).

Outcome

Open. The difference between Parkinson's brains (52%) and ageing controls (43%) was modest compared with the spread within each group (each ± 9.3%), and the data show association, not proof that deletions cause the cell loss. Kraytsberg's authors say only that deletions "may be directly responsible" for impaired respiration. No treatment that prevents or repairs mtDNA damage has reached Parkinson's trials in the sources checked.

Sources

• Bender et al., Nat Genet 2006;38:515–517, DOI 10.1038/ng1769, PMID 16604074 (abstract via PubMed; funded by the Wellcome Trust and Medical Research Council per PubMed)
• Kraytsberg et al., Nat Genet 2006;38:518–520, DOI 10.1038/ng1778, PMID 16604072, "Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons" (abstract via Europe PMC)
• Alzforum news, "DNA Deletions Sap Mitochondria in Parkinson Neurons" (source of the 43%/52% figures, the nine donors and the 60% caveat)
• Not yet verified: the number of brains in the Newcastle paper; the nine-donor, 33-to-102 and 60% details (Alzforum report only; full texts not read); whether commentators disagreed on how central the deletions are (earlier text, no source re-found); whether later work confirmed causation.