[Abstract Title]. - Society for Neuroscience

Abstract: Mitochondrial dynamics (fission/fusion and transport) are important in synapse
formation, mitochondrial DNA maintenance, and cell death mechanisms, and are increasingly
linked to neurodegenerative diseases. In Parkinson‟s disease (PD), where mitochondrial
dysfunction is implicated, the dynamic properties of mitochondria may be important in the
degeneration of susceptible axons. In fact, genetic studies have suggested a role for PD-related
genes in mitochondrial dynamics (Poole et al and Yang et al, PNAS, 2008). We have previously
developed methodology for directly quantifying mitochondrial dynamics in living neurons, and
in order to examine mitochondrial dynamics in models of PD, we first developed a chronic
rotenone model of PD in differentiated dopaminergic cells. NGF-differentiated PC6-3 cells were
treated with vehicle or low concentrations of rotenone. Chronic treatment with up to 10 nM
rotenone for 3 weeks did not result in an increase in cell death over control conditions, and 3
weeks of 25 nM rotenone treatment resulted in minimal cell death. However, similar to patients
with PD and animal models, our chronic low-dose rotenone treatment resulted in significant loss
of neuronal processes, which may represent early toxicity. We then asked whether altering
mitochondrial dynamics could influence these pathologic changes by altering the mitochondrial
fission mediator Drp1. One could hypothesize either that inhibition or promotion of fission could
be protective in PD. We found that overexpression of the dominant-negative form of Drp1,
dnDrp1 K38A , which inhibits mitochondrial fission in neurons, protected against the loss of
neuronal processes caused by 2 and 3 week treatment with 5 and 25 nM rotenone. This supports
a role for mitochondrial dynamics in the early pathologic changes in PD.
Because PD is a disease of aging neurons, yet little is known about age-related changes in
mitochondrial dynamics, we also directly characterized mitochondrial dynamics as neurons age.
Using methodology we previously developed (utilizing mitochondrially targeted DsRed2 and
photoactivatable GFP and direct live imaging of fusion, fission, and transport), we quantified
mitochondrial dynamics in rat cortical neurons as they aged in culture. The rate of mitochondrial
fission in neuronal processes was higher at 7 days (young neurons) than at 14 or 28 days, with
the lowest ratio of fission to fusion at 14 days (mature neurons), which may reflect the role of
fission in mitochondrial distribution and synapse formation. Similar dynamic processes can be
observed in a chronic PD model, and their characterization may help in elucidating the role of
mitochondrial dynamics in PD.
Disclosures: S.B. Berman, None; B.A. Arnold, None.
Poster
253. Parkinson's Disease Models: Neuroprotective Mechanisms I
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 253.7/X8
Topic: C.11.j. Neuroprotective mechanisms: Parkinson‟s disease models