VMAT2 and dopamine storage

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

Caudle et al. (Gary Miller's group, Emory University, with Donato Di Monte and Piers Emson), J Neurosci 2007; Lohr et al. (Kristen Lohr, Amy Bernstein, Miller and colleagues), PNAS 2014. All three papers list US NIH extramural support (NIEHS, with NINDS and others on the later two); no company or other funder was found.

What happened

Dopamine is made in the cytosol (the cell's inner fluid) and must be packed into small vesicles by the vesicular monoamine transporter 2 (VMAT2). Free dopamine in the cytosol (the cell's inner fluid) is reactive and toxic. See also landmark 22 for dopamine itself.

• Caudle 2007: mice making about 5% of normal VMAT2 ("VMAT2 LO") showed age-related damage to the nigra-to-striatum pathway: more oxidised dopamine products, less dopamine and dopamine transporter, more alpha-synuclein, a behavioural deficit that levodopa relieved, and loss of neurons in the substantia nigra pars compacta in old animals.
• Lohr 2014: mice with a twofold increase in vesicular transport (a BAC transgene carrying extra VMAT2) had 56% more vesicular dopamine capacity and 84% more stimulated dopamine release. After MPTP (landmark 2) they had less terminal damage and less nigral cell loss.
• Lohr 2016 (Toxicol Sci) put both mouse lines on one genetic background and confirmed the result: roughly 95% lower VMAT2 gave progressive terminal loss and worse MPTP damage; high VMAT2 protected. This is the same group, not an independent one.
• People. Pifl and colleagues (2023, npj Parkinsons Dis) report that dopamine storage in striatal vesicles from people with idiopathic Parkinson's is impaired, and that VMAT2 binding and dopamine uptake are also reduced in brains with incidental Lewy body disease (Lewy bodies in people with no symptoms), which they read as an early change.

Why it moved us toward a cure

It gives a testable reason why dopamine neurons, and not other cells, are exposed: they carry their own toxin, and safe storage is the guard. It also points to a drug route, raising vesicular capacity, that is different from lowering synuclein. It feeds the cytosolic-dopamine argument in landmark 269.

Outcome

Open. The mouse findings are consistent, but come from one group and from engineered VMAT2 levels. The human data show impaired vesicular storage in the disease, not that it causes it. No VMAT2-enhancing drug was found. No correction or retraction was found for any of the three papers (Crossref, Europe PMC).

Sources

• Caudle et al., J Neurosci 2007;27:8138–8148, DOI 10.1523/JNEUROSCI.0319-07.2007
• Lohr et al., PNAS 2014;111:9977–9982, DOI 10.1073/pnas.1402134111
• Lohr et al., Toxicol Sci 2016;153:79–88, DOI 10.1093/toxsci/kfw106
• Pifl et al., npj Parkinsons Dis 2023;9:89, DOI 10.1038/s41531-023-00514-z (abstract read)
• Not yet verified: full texts (abstracts only); the exact nigral cell-loss percentages in either paper; independent replication of the VMAT2 mouse lines outside the Miller group; any VMAT2-raising drug in development.