24 August 2012. Tau is toxic to neurons, but exactly how is not crystal clear. A new study in the August 23 Neuron suggests that tau overexpression indirectly elongates mitochondria, which then malfunction and cause cell death. Mel Feany, Harvard Medical School, and colleagues found that in fruit flies, tau binds and stabilizes the cytoskeletal protein F-actin, preventing a key mitochondrial fission protein from reaching the organelles. The mechanism could be one of several that sabotage mitochondria, leading to cell death. "Overall, it is very compelling evidence demonstrating that tau overexpression causes mitochondrial elongation in Drosophila," said Xiongwei Zhu, Case Western Reserve University, Cleveland, Ohio, who was not involved in the study.
A delicate balance of mergers and divisions, known respectively as fusion and fission, maintain mitochondria at just the right length. If that balance goes out of whack, there can be serious consequences for cell health. Abnormal mitochondria have been implicated in several neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases (see ARF related news story) as well as Huntington's disease (see ARF related news story) and ALS (see ARF related news story).
Mitochondria move about the cell via tethers to cytoskeletal actin and microtubule filaments. Feany's lab previously found that phosphorylated tau binds to and stabilizes filamentous (F) actin in both human tau-expressing flies and mice (see ARF related news story on Fulga et al., 2007). This led to bundled, rod-like actin and neurodegeneration, but it was unclear how the neurons died.
To probe that question, first author Brian DuBoff expressed human tau with an FTDP-17-linked missense mutation (R406W) in fruit flies. Using laser-scanning confocal microscopy, he saw neuronal mitochondria that were more than twice as long in transgenic flies as controls, suggesting an abnormally low amount of fission. Cell death followed shortly thereafter. Mitochondria also appeared to be elongated in rTg4510 and K3 mouse neurons expressing human tau with P301L or K369I mutations, respectively. Compared to controls, brains from animals expressing tau produced more superoxide. This result implied that the longer mitochondria promoted oxidative stress, leading to cell death.
What extended the mitochondria? To divide, the organelles use a fission-driving dynamin-related GTPase called DRP1, which keeps mitochondria small. In control, but not in tau transgenic flies, DRP1 latched onto the organelles, but it appeared that F-actin stabilization prevented DRP1 from reaching the mitochondria in tau transgenics. To confirm that F-actin bundles were responsible, DuBoff used two pro-bundling proteins, WASP and forked, to stabilize actin. Like human tau, these proteins caused mitochondria to stretch, and the organelles lacked DRP1. The GTPase instead accumulated on F-actin. The findings suggest that DRP1 accumulates more on the stabilized form of F-actin, and then fails to reach the mitochondria.
What mediates the DRP1 and mitochondria interaction? Myosins, which are motor proteins, are known to tether both proteins and organelles to actin, or even move them along actin strands. To find out if myosins were involved, the group looked at eight myosin fly knockouts currently available to find out if one type led to the distended mitochondria. Only mutations in fly homologues of mammalian myosin II heavy and light chains promoted long mitochondria that seemed short on DRP1. Fewer mitochondria co-precipitated with F-actin in myosin II knockouts, suggesting that the myosin homologues attach the organelles to F-actin, where they can then bind DRP1.
"One idea we favor is that with increased F-actin, either the mitochondria or the DRP1 cannot be appropriately transported, and thus DRP1 cannot translocate to mitochondria," said Feany. But there are other possibilities, she said, including an atypical F-actin orientation that impairs interactions. "The exact mechanism remains the subject of future study," she added.
The result could extend recent findings from Lennart Mucke and colleagues at the Gladstone Institute of Neurological Disease in San Francisco, California, who found that an absence of tau prevents Aβ's toxic dampening of mitochondrial transport (see ARF related news story on Vossel et al., 2010), said ShiDu Yan, University of Kansas, Lawrence. Based on the current report, a deficit in mitochondrial morphology could also be blocked by depletion of tau.
Could the same process be going on in humans? "The fact that we replicated many of the Drosophila findings in mouse tauopathy models suggests it could be going on in mammals," Feany said. In addition, Zhu and colleagues observed DRP1 suppression and elongated mitochondria in fibroblasts from AD patients (see Wang et al., 2008), suggesting a similar chain of events may unfold in people with Alzheimer’s. But it is impossible to know until the model is tested in humans, Feany said. "This paper helps us to understand the DRP1-actin link and a basic mechanism, but relevance to disease states such as Alzheimer's is unclear," said Hemachandra Reddy, Oregon Science and Health University, Beaverton.
There are other hints that DRP1 may be awry in AD. Reddy found recently that phosphorylated tau might bind directly to DRP1 and cause mitochondrial fragmentation (see Manczak and Reddy, 2012). Aβ may exert its own effect on DRP1 as well, by driving nitric oxide production, which drives DRP1-induced fission and mitochondrial fragmentation (see ARF related news story). It still is not clear whether mitochondria are fragmented or elongated in human disease, or how Aβ pathology influences mitochondrial length. "We need more research in that direction," said Reddy.—Gwyneth Dickey Zakaib.
DuBoff B, Götz J, Feany MB. Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo. Neuron 2012 Aug 23; 75, 618-632. Abstract