- Email: [email protected]
α-Synuclein and Tau: Mitochondrial Kill Switches
Neuron
Previews a-Synuclein and Tau: Mitochondrial Kill Switches Ulrike Pech1,2 and Patrik Verstreken1,2,* 1VIB-KU
Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2017.12.024 2KU
a-Synuclein resides in Lewy bodies in Parkinson’s disease. Ordonez et al. (2017) now show that a-syn disrupts the actin network, causing Drp1-dependent mitochondrial fission defects. This is similar to defects induced by the PD risk factor Tau, suggesting converging pathways in neurodegeneration. Alzheimer’s (AD) and Parkinson’s disease (PD) affect millions of people around the world and constitute the most common neurodegenerative diseases worldwide. The pathways underlying the cause of these diseases remain enigmatic and cures do not exist. AD and PD are characterized by protein inclusions in the brain: in AD, Ab plaques that accumulate mostly extracellularly and Tau tangles that accumulate intracellularly; in PD, Lewy bodies that are rich in a-synuclein (a-syn). Interestingly, Tau is also mutated in frontotemporal dementia with PD and is one of the major risk factors in PD. Despite the disease connections between Tau and a-syn, the processes and pathways they affect and that eventually lead to neurodegeneration remain largely elusive. The Feany lab now adds an important piece to the puzzle. They not only connect cellular phenotypes of a-syn to rearrangements of the actin cytoskeleton and to mitochondrial dysfunction in vivo, but they also highlight mechanistic similarities between a-syn and Tau toxicity, suggesting common underlying pathways. Although the familial causes for AD and PD are rare, pathogenic mutations provide an inroad to model these diseases in animals, allowing researchers to unravel how the nervous system is affected. Mutations and triplications of the a-syn gene were the first genetic causes of PD discovered, suggesting the expression levels of a-syn need to be tightly regulated under normal conditions. This principle of excess a-syn causing PD was a feature initially exploited by Mel Feany almost 20 years ago to build the first Drosophila model of PD (Feany and Bender, 2000). Overexpressing wild-type or mutant human a-syn in the entire nervous system of the fruit fly recapitulates cardinal symp-
toms of human PD patients, including impaired startle-induced locomotion, decreased fitness and survival, and the loss of dopaminergic synapses in the central brain (Feany and Bender, 2000; Riemensperger et al., 2013). The improved model presented by Ordonez et al. in this issue of Neuron recapitulates these features as well. Genetic analyses of familial PD over the past years have revealed numerous mutations in more than 20 different genes (e.g., Houlden and Singleton, 2012). Most of these ‘‘PD genes’’ are highly conserved across species and many exist also in the fruit fly genome. In most of the cases tested, expression of the human homolog in fly null mutants rescues the fly phenotypes, indicating the human and fly proteins hold common functions (Vanhauwaert and Verstreken, 2015). It is currently not clear if the variety of proteins these genes encode act in overlapping pathways, including if they interact with a-syn. However, a critical effect on mitochondrial integrity seems to be emerging for at least some of the PD genes, and the work by Ordonez now further implicates a-syn in this mitochondrial pathway as well. This is interesting because the (few) environmental models that are used to mimic PD pathology interfere with mitochondrial function, and sporadic patients have also been shown to often display mitochondrial dysfunction (Ryan et al., 2015). The most widely used models are MPTP and the pesticide rotenone that block complex 1 function of the mitochondrial electron transport chain. While these toxin models may not recapitulate the exact molecular dysfunction elicited by ‘‘classical PD,’’ they do point to an important mitochondrial component in at least some PD cases.
The toxin animal models and familial models of PD in which mitochondrial dysfunction has been firmly established (e.g., parkin mutations) rarely show Lewy-like bodies, suggesting that the mechanisms of a-syn toxicity act, at least partially, upstream of mitochondrial dysfunction (Houlden and Singleton, 2012; Ryan et al., 2015). Recent reports have increasingly started to point toward links between a-syn toxicity, cytoskeleton dynamics, and dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics (Pellegrini et al., 2017). However, a conclusive and direct connection has been missing. Ordonez et al. now fill this gap and show that a-syn alters F-actin dynamics by binding to spectrin. This mislocalizes Drp1 and consequently impairs Drp1-mediated mitochondrial fission, a prerequisite to maintain normal mitochondrial form and function in neurons. Ordonez et al. arrived at their conclusions by first implementing a new fly a-syn PD model. They generated animals that express a-syn at a level comparable to that seen in human brain tissue. These flies show a-syn aggregation in the brain, neurodegeneration in the optic lobes, accelerated loss of climbing ability, and early death. Previous studies by the Feany lab and others indicated a correlation between F-actin dynamics and a-syn toxicity, and the authors indeed confirm excess levels of F-actin and actin aggregates in their fly model, but also in mice overexpressing human A53T mutant a-syn and in cortex tissue of a-synucleinopathy patients. Genetically decreasing F-actin levels rescues the phenotypes in the a-syn flies, while increasing F-actin worsened them. These results indicate the actin defect is evolutionary conserved
Neuron 97, January 3, 2018 ª 2017 Elsevier Inc. 3
Neuron
Previews
by mitochondrial dysfunction and subsequent neurodegeneration. This provides a possible roadmap to further unravel the defects caused by a multitude of PD-causing mutations that all lead to common disease features. Pathologically, several of these PD cases are associated with a-syn inclusions; however, what leads to excess expression and/or phosphorylation of a-syn in these PD patients remains a question to be answered in future studies. Figure 1. Model of the Defects Proposed to be Common to a-syn and Tau Models
Both phosphorylated a-syn and Tau impair cytoskeleton dynamics, in turn leading to disrupted Drp1mediated mitochondrial fission and defects in mitochondrial integrity.
and relevant to the pathology-like defects in the animal model. F-actin dynamics were previously shown to regulate mitochondrial fission. Reasoning that mitochondrial dysfunction is a recurrent theme in PD, Ordonez et al. show that the disruption of F-actin dynamics is caused by a-syn expression and disrupts the localization of Drp1 to mitochondria, and thus proper mitochondrial fission in flies and mouse models. These results bring strong evidence that a-syn acts upstream of impaired actin dynamics and mitochondrial dysfunction. Providing mechanistic insight, they identify the actin-crosslinking protein spectrin as the missing link between a-syn and the regulation of actin dynamics. This appears to be dependent on the phosphorylation of a-syn, a post-translational modification associated with PD (Taymans and Baekelandt, 2014). Interestingly, overexpression of a-spectrin rescues a-syn toxicity by redirecting a-syn-spectrin complexes into insoluble inclusions, suggesting a protective role of inclusion-formation by protecting the F-actin skeleton from the defects induced by a-syn. Remarkably, the authors previously showed a very similar mechanism underlying aspects of Tau pathology (DuBoff et al., 2012), whereby expression of Tau
4 Neuron 97, January 3, 2018
mis-stabilized F-actin and impaired the ability of Drp1 to localize to mitochondria. In their current work, Ordonez et al. show that co-expressing a-syn and Tau significantly enhances the phenotypes of each model alone, suggesting that the pathways underlying a-syn and Tau toxicity converge onto a common knot, i.e., F-actin stabilization (Figure 1). More broadly, the Ordonez et al. study further supports the notion that, at its earliest stages, neurodegeneration affects the synapse and provides some inroads as to why some synapses are more vulnerable than others, as not all synapses contain mitochondria. F-actin stabilization defects will likely also cause broader effects as well. In neurons, where synapses are often far from cell bodies, axonal transport and synaptic vesicle release and turnover come to mind as processes that depend heavily on the cytoskeleton. Indeed, a-syn is a synaptic protein that binds with synaptic vesicles, and a recent study from our lab showed that pathological Tau increases F-actin levels in the presynaptic compartment and crosslinks F-actin with vesicles to impair presynaptic function in early disease stages (Zhou et al., 2017). The results by Ordonez et al. point to an important function of the neuronal cytoskeleton in the pathogenesis mediated
REFERENCES DuBoff, B., Go¨tz, J., and Feany, M.B. (2012). Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75, 618–632. Feany, M.B., and Bender, W.W. (2000). A Drosophila model of Parkinson’s disease. Nature 404, 394–398. Houlden, H., and Singleton, A.B. (2012). The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol. 124, 325–338. Ordonez, D.G., Lee, M.K., and Feany, M.B. (2017). a-synuclein induces mitochondrial dysfunction through spectrin and the actin cytoskeleton. Neuron 97, this issue, 108–124. Pellegrini, L., Wetzel, A., Granno´, S., Heaton, G., and Harvey, K. (2017). Back to the tubule: microtubule dynamics in Parkinson’s disease. Cell. Mol. Life Sci. 74, 409–434. Riemensperger, T., Issa, A.R., Pech, U., Coulom, H., Nguyễn, M.V., Cassar, M., Jacquet, M., Fiala, A., and Birman, S. (2013). A single dopamine pathway underlies progressive locomotor deficits in a Drosophila model of Parkinson disease. Cell Rep. 5, 952–960. Ryan, B.J., Hoek, S., Fon, E.A., and Wade-Martins, R. (2015). Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem. Sci. 40, 200–210. Taymans, J.M., and Baekelandt, V. (2014). Phosphatases of a-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism. Front. Genet. 5, 382. Vanhauwaert, R., and Verstreken, P. (2015). Flies with Parkinson’s disease. Exp. Neurol. 274 (Pt A), 42–51. Zhou, L., McInnes, J., Wierda, K., Holt, M., Herrmann, A.G., Jackson, R.J., Wang, Y.C., Swerts, J., Beyens, J., Miskiewicz, K., et al. (2017). Tau association with synaptic vesicles causes presynaptic dysfunction. Nat. Commun. 8, 15295.
Previews a-Synuclein and Tau: Mitochondrial Kill Switches Ulrike Pech1,2 and Patrik Verstreken1,2,* 1VIB-KU
Leuven Center for Brain and Disease Research, 3000 Leuven, Belgium Leuven, Department of Neurosciences, Leuven Brain Institute, 3000 Leuven, Belgium *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2017.12.024 2KU
a-Synuclein resides in Lewy bodies in Parkinson’s disease. Ordonez et al. (2017) now show that a-syn disrupts the actin network, causing Drp1-dependent mitochondrial fission defects. This is similar to defects induced by the PD risk factor Tau, suggesting converging pathways in neurodegeneration. Alzheimer’s (AD) and Parkinson’s disease (PD) affect millions of people around the world and constitute the most common neurodegenerative diseases worldwide. The pathways underlying the cause of these diseases remain enigmatic and cures do not exist. AD and PD are characterized by protein inclusions in the brain: in AD, Ab plaques that accumulate mostly extracellularly and Tau tangles that accumulate intracellularly; in PD, Lewy bodies that are rich in a-synuclein (a-syn). Interestingly, Tau is also mutated in frontotemporal dementia with PD and is one of the major risk factors in PD. Despite the disease connections between Tau and a-syn, the processes and pathways they affect and that eventually lead to neurodegeneration remain largely elusive. The Feany lab now adds an important piece to the puzzle. They not only connect cellular phenotypes of a-syn to rearrangements of the actin cytoskeleton and to mitochondrial dysfunction in vivo, but they also highlight mechanistic similarities between a-syn and Tau toxicity, suggesting common underlying pathways. Although the familial causes for AD and PD are rare, pathogenic mutations provide an inroad to model these diseases in animals, allowing researchers to unravel how the nervous system is affected. Mutations and triplications of the a-syn gene were the first genetic causes of PD discovered, suggesting the expression levels of a-syn need to be tightly regulated under normal conditions. This principle of excess a-syn causing PD was a feature initially exploited by Mel Feany almost 20 years ago to build the first Drosophila model of PD (Feany and Bender, 2000). Overexpressing wild-type or mutant human a-syn in the entire nervous system of the fruit fly recapitulates cardinal symp-
toms of human PD patients, including impaired startle-induced locomotion, decreased fitness and survival, and the loss of dopaminergic synapses in the central brain (Feany and Bender, 2000; Riemensperger et al., 2013). The improved model presented by Ordonez et al. in this issue of Neuron recapitulates these features as well. Genetic analyses of familial PD over the past years have revealed numerous mutations in more than 20 different genes (e.g., Houlden and Singleton, 2012). Most of these ‘‘PD genes’’ are highly conserved across species and many exist also in the fruit fly genome. In most of the cases tested, expression of the human homolog in fly null mutants rescues the fly phenotypes, indicating the human and fly proteins hold common functions (Vanhauwaert and Verstreken, 2015). It is currently not clear if the variety of proteins these genes encode act in overlapping pathways, including if they interact with a-syn. However, a critical effect on mitochondrial integrity seems to be emerging for at least some of the PD genes, and the work by Ordonez now further implicates a-syn in this mitochondrial pathway as well. This is interesting because the (few) environmental models that are used to mimic PD pathology interfere with mitochondrial function, and sporadic patients have also been shown to often display mitochondrial dysfunction (Ryan et al., 2015). The most widely used models are MPTP and the pesticide rotenone that block complex 1 function of the mitochondrial electron transport chain. While these toxin models may not recapitulate the exact molecular dysfunction elicited by ‘‘classical PD,’’ they do point to an important mitochondrial component in at least some PD cases.
The toxin animal models and familial models of PD in which mitochondrial dysfunction has been firmly established (e.g., parkin mutations) rarely show Lewy-like bodies, suggesting that the mechanisms of a-syn toxicity act, at least partially, upstream of mitochondrial dysfunction (Houlden and Singleton, 2012; Ryan et al., 2015). Recent reports have increasingly started to point toward links between a-syn toxicity, cytoskeleton dynamics, and dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics (Pellegrini et al., 2017). However, a conclusive and direct connection has been missing. Ordonez et al. now fill this gap and show that a-syn alters F-actin dynamics by binding to spectrin. This mislocalizes Drp1 and consequently impairs Drp1-mediated mitochondrial fission, a prerequisite to maintain normal mitochondrial form and function in neurons. Ordonez et al. arrived at their conclusions by first implementing a new fly a-syn PD model. They generated animals that express a-syn at a level comparable to that seen in human brain tissue. These flies show a-syn aggregation in the brain, neurodegeneration in the optic lobes, accelerated loss of climbing ability, and early death. Previous studies by the Feany lab and others indicated a correlation between F-actin dynamics and a-syn toxicity, and the authors indeed confirm excess levels of F-actin and actin aggregates in their fly model, but also in mice overexpressing human A53T mutant a-syn and in cortex tissue of a-synucleinopathy patients. Genetically decreasing F-actin levels rescues the phenotypes in the a-syn flies, while increasing F-actin worsened them. These results indicate the actin defect is evolutionary conserved
Neuron 97, January 3, 2018 ª 2017 Elsevier Inc. 3
Neuron
Previews
by mitochondrial dysfunction and subsequent neurodegeneration. This provides a possible roadmap to further unravel the defects caused by a multitude of PD-causing mutations that all lead to common disease features. Pathologically, several of these PD cases are associated with a-syn inclusions; however, what leads to excess expression and/or phosphorylation of a-syn in these PD patients remains a question to be answered in future studies. Figure 1. Model of the Defects Proposed to be Common to a-syn and Tau Models
Both phosphorylated a-syn and Tau impair cytoskeleton dynamics, in turn leading to disrupted Drp1mediated mitochondrial fission and defects in mitochondrial integrity.
and relevant to the pathology-like defects in the animal model. F-actin dynamics were previously shown to regulate mitochondrial fission. Reasoning that mitochondrial dysfunction is a recurrent theme in PD, Ordonez et al. show that the disruption of F-actin dynamics is caused by a-syn expression and disrupts the localization of Drp1 to mitochondria, and thus proper mitochondrial fission in flies and mouse models. These results bring strong evidence that a-syn acts upstream of impaired actin dynamics and mitochondrial dysfunction. Providing mechanistic insight, they identify the actin-crosslinking protein spectrin as the missing link between a-syn and the regulation of actin dynamics. This appears to be dependent on the phosphorylation of a-syn, a post-translational modification associated with PD (Taymans and Baekelandt, 2014). Interestingly, overexpression of a-spectrin rescues a-syn toxicity by redirecting a-syn-spectrin complexes into insoluble inclusions, suggesting a protective role of inclusion-formation by protecting the F-actin skeleton from the defects induced by a-syn. Remarkably, the authors previously showed a very similar mechanism underlying aspects of Tau pathology (DuBoff et al., 2012), whereby expression of Tau
4 Neuron 97, January 3, 2018
mis-stabilized F-actin and impaired the ability of Drp1 to localize to mitochondria. In their current work, Ordonez et al. show that co-expressing a-syn and Tau significantly enhances the phenotypes of each model alone, suggesting that the pathways underlying a-syn and Tau toxicity converge onto a common knot, i.e., F-actin stabilization (Figure 1). More broadly, the Ordonez et al. study further supports the notion that, at its earliest stages, neurodegeneration affects the synapse and provides some inroads as to why some synapses are more vulnerable than others, as not all synapses contain mitochondria. F-actin stabilization defects will likely also cause broader effects as well. In neurons, where synapses are often far from cell bodies, axonal transport and synaptic vesicle release and turnover come to mind as processes that depend heavily on the cytoskeleton. Indeed, a-syn is a synaptic protein that binds with synaptic vesicles, and a recent study from our lab showed that pathological Tau increases F-actin levels in the presynaptic compartment and crosslinks F-actin with vesicles to impair presynaptic function in early disease stages (Zhou et al., 2017). The results by Ordonez et al. point to an important function of the neuronal cytoskeleton in the pathogenesis mediated
REFERENCES DuBoff, B., Go¨tz, J., and Feany, M.B. (2012). Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75, 618–632. Feany, M.B., and Bender, W.W. (2000). A Drosophila model of Parkinson’s disease. Nature 404, 394–398. Houlden, H., and Singleton, A.B. (2012). The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol. 124, 325–338. Ordonez, D.G., Lee, M.K., and Feany, M.B. (2017). a-synuclein induces mitochondrial dysfunction through spectrin and the actin cytoskeleton. Neuron 97, this issue, 108–124. Pellegrini, L., Wetzel, A., Granno´, S., Heaton, G., and Harvey, K. (2017). Back to the tubule: microtubule dynamics in Parkinson’s disease. Cell. Mol. Life Sci. 74, 409–434. Riemensperger, T., Issa, A.R., Pech, U., Coulom, H., Nguyễn, M.V., Cassar, M., Jacquet, M., Fiala, A., and Birman, S. (2013). A single dopamine pathway underlies progressive locomotor deficits in a Drosophila model of Parkinson disease. Cell Rep. 5, 952–960. Ryan, B.J., Hoek, S., Fon, E.A., and Wade-Martins, R. (2015). Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem. Sci. 40, 200–210. Taymans, J.M., and Baekelandt, V. (2014). Phosphatases of a-synuclein, LRRK2, and tau: important players in the phosphorylation-dependent pathology of Parkinsonism. Front. Genet. 5, 382. Vanhauwaert, R., and Verstreken, P. (2015). Flies with Parkinson’s disease. Exp. Neurol. 274 (Pt A), 42–51. Zhou, L., McInnes, J., Wierda, K., Holt, M., Herrmann, A.G., Jackson, R.J., Wang, Y.C., Swerts, J., Beyens, J., Miskiewicz, K., et al. (2017). Tau association with synaptic vesicles causes presynaptic dysfunction. Nat. Commun. 8, 15295.