Virus-driven synuclein rat and marmoset models

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

Deniz Kirik, Anders Björklund and colleagues at the Wallenberg Neuroscience Center, Lund University, with Nicholas Muzyczka and Ronald Mandel (virus vector experts). The monkey study added Lucy Annett. Funders were not checked.

What happened

Mice carrying human synuclein genes (for example landmark 31) had not reproduced loss of the nigral dopamine neurons. Kirik's group instead injected recombinant adeno-associated virus (rAAV, a gene-delivery vector) into the substantia nigra, the midbrain region where these neurons sit. In rats (J Neurosci 2002) the vector delivered normal or A53T human synuclein for up to six months. Nigral dopamine cell loss ranged from 30% to 80%, striatal dopamine fell 40–50%, and movement problems appeared once loss passed roughly 50–60%. Unexpectedly, the cell-body and axon pathology had subsided by six months even though synuclein levels stayed high. In marmosets (PNAS 2003), 8 animals were used: 2 given normal and 2 given A53T human synuclein, 4 given a control vector; one synuclein animal had a failed injection, leaving 3 analysed. Synuclein appeared in 90–95% of nigral dopamine neurons. By 16 weeks 32–61% of tyrosine hydroxylase-positive (dopamine) neurons were lost (the abstract says 30–60%), with synuclein-positive inclusions and swollen, fragmented nerve fibres, and a head-position bias.

Why it moved us toward a cure

It showed that simply having too much synuclein in these neurons is toxic to them, matching human families with extra gene copies (landmark 14), and it offered a model in which drugs aimed at synuclein could be tested for protecting neurons. The marmoset work was an early primate version, and the authors called it a "new" primate model (they did not claim it was the first).

Outcome

Advanced. The same Lund group used the rat model to show that the cell loss tracked a decline in lysosome function and that boosting the lysosome regulator TFEB protected neurons (Decressac et al., PNAS 2013). Limits: the marmoset study is very small, and in rats the pathology faded by six months, so these models overproduce synuclein in a way that may differ from slow human disease.

Sources

• Kirik et al., J Neurosci 2002;22:2780–2791 (Lund University record)
• Kirik et al., PNAS 2003;100:2884–2889, DOI 10.1073/pnas.0536383100 (PMC151435)
• Decressac et al., PNAS 2013;110:E1817–E1826, DOI 10.1073/pnas.1305623110, PMID 23610405
• Kirik et al., J Neurosci 2002, DOI 10.1523/JNEUROSCI.22-07-02780.2002, PMID 11923443 (abstract)
• Not yet verified: funders; whether any earlier adult-animal synuclein cell-loss model exists; later primate AAV-synuclein work; current use of these models for drug testing beyond Decressac 2013.