Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Neuron (Impact Factor: 15.05). 08/2012; 75(4):618-32. DOI: 10.1016/j.neuron.2012.06.026
Source: PubMed


Mitochondrial abnormalities have been documented in Alzheimer's disease and related neurodegenerative disorders, but the causal relationship between mitochondrial changes and neurodegeneration, and the specific mechanisms promoting mitochondrial dysfunction, are unclear. Here, we find that expression of human tau results in elongation of mitochondria in both Drosophila and mouse neurons. Elongation is accompanied by mitochondrial dysfunction and cell cycle-mediated cell death, which can be rescued in vivo by genetically restoring the proper balance of mitochondrial fission and fusion. We have previously demonstrated that stabilization of actin by tau is critical for neurotoxicity of the protein. Here, we demonstrate a conserved role for actin and myosin in regulating mitochondrial fission and show that excess actin stabilization inhibits association of the fission protein DRP1 with mitochondria, leading to mitochondrial elongation and subsequent neurotoxicity. Our results thus identify actin-mediated disruption of mitochondrial dynamics as a direct mechanism of tau toxicity in neurons in vivo.

12 Reads
  • Source
    • "Down-regulation of Drp1 and mitochondrial elongation can be caused by a pharmacological DNA damage inducer [88] and cellular senescence [101], which mechanistically links ageing with reduced mitochondrial bioenergetics. Overexpression of AD associated protein, Tau, prevents Drp1 localisation to mitochondria [102] demonstrating that localisation as well as expression of mitochondrial morphology regulators is important in cellular quality control. Metabolic health may also be influenced by alterations in mitochondrial morphology with skeletal muscle expression of Mfn-2 being increased with exercise [103] and downregulated in obese mice [104] suggesting a link between energy metabolism and mitochondrial morphology transitions. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial dysfunction has been implicated in the aetiology of many complex diseases, as well as the ageing process. Much of the research on mitochondrial dysfunction has focused on how mitochondrial damage may potentiate pathological phenotypes. The purpose of this review is to draw attention to the less well-studied mechanisms by which the cell adapts to mitochondrial perturbations. This involves communication of stress to the cell and successful induction of quality control responses, which include mitophagy, unfolded protein response, upregulation of antioxidant and DNA repair enzymes, morphological changes, and if all else fails apoptosis. The mitochondrion is an inherently stressful environment and we speculate that dysregulation of stress signaling or an inability to switch on these adaptations during times of mitochondrial stress may underpin mitochondrial dysfunction and hence amount to pathological states over time.
    International Journal of Cell Biology 01/2014; 2014(51):156020. DOI:10.1155/2014/156020
  • Source
    • "p66Shc also mediates β-amyloid neurotoxicity [167] and is required for successful ischemic preconditioning in mixed neuron/glia cultures [168]. 5. p53 and mitochondrial dynamics (Fig. 2C) Maintaining proper mitochondrial length is essential for normal mitochondrial function in neurons and dysregulated mitochondrial dynamics has been associated with neuropathological conditions [169] [170] [171]. Mitochondrial fusion and fission affect bioenergetic efficiency and both excessive and impaired fission or fusion lead to mitochondrial dysfunction [172] [173] [174] [175]. Specifically, excessive mitochondrial fission or fragmentation is associated with and often causally related to neuronal cell death caused by a variety of experimental toxic stressors [176] [177] [178] [179]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The p53 tumor suppressor plays a central role in dictating cell survival and death as a cellular sensor for a myriad of stresses including DNA damage, oxidative and nutritional stress, ischemia and disruption of nucleolar function. Activation of p53-dependent apoptosis leads to mitochondrial apoptotic changes via the intrinsic and extrinsic pathways triggering cell death execution most notably by release of cytochrome c and activation of the caspase cascade. Although it was previously believed that p53 induces apoptotic mitochondrial changes exclusively through transcription-dependent mechanisms, recent studies suggest that p53 also regulates apoptosis via a transcription-independent action at the mitochondria. Recent evidence further suggests that p53 can regulate necrotic cell death and autophagic activity including mitophagy. An increasing number of cytosolic and mitochondrial proteins involved in mitochondrial metabolism and respiration are regulated by p53, which influences mitochondrial ROS production as well. Cellular redox homeostasis is also directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. Proper regulation of mitochondrial size and shape through fission and fusion assures optimal mitochondrial bioenergetic function while enabling adequate mitochondrial transport to accommodate local energy demands unique to neuronal architecture. Abnormal regulation of mitochondrial dynamics has been increasingly implicated in neurodegeneration, where elevated levels of p53 may have a direct contribution as the expression of some fission/fusion proteins are directly regulated by p53. Thus, p53 may have a much wider influence on mitochondrial integrity and function than one would expect from its well-established ability to transcriptionally induce mitochondrial apoptosis. However, much of the evidence demonstrating that p53 can influence mitochondria through nuclear, cytosolic or intra-mitochondrial sites of action has yet to be confirmed in neurons. Nonetheless, as mitochondria are essential for supporting normal neuronal functions and in initiating/propagating cell death signaling, it appears certain that the mitochondria-related functions of p53 will have broader implications than previously thought in acute and progressive neurological conditions, providing new therapeutic targets for treatment. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction and Neurodegenerative Diseases.
    Biochimica et Biophysica Acta 01/2014; 1842(8). DOI:10.1016/j.bbadis.2013.12.015 · 4.66 Impact Factor
    • "Genes involved in actin pathways, such as CD2AP (CD2-associated protein), may directly impact mitochondrial fission, fusion, and transport along axons due to the dynamic actin remodeling and stabilization required for these processes [78]. Impairment of mitochondrial fission , fusion, and axonal transport can promote abnormal hyperphosphorylation of MAPT (microtubule-associated protein tau), leading to the accumulation of dysfunctional mitochondria and the induction of apoptosis due to poor cellular energetics [79] [80] [81]. Components of the mitochondrial membrane are also important for normal functioning through regulation of molecular flux. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The discovery of causative genetic mutations in affected family members has historically dominated our understanding of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Nevertheless, most cases of neurodegenerative disease are not explained by Mendelian inheritance of known genetic variants, but instead are thought to have a complex etiology with numerous genetic and environmental factors contributing to susceptibility. Although unbiased genome-wide association studies (GWAS) have identified novel associations to neurodegenerative diseases, most of these hits explain only modest fractions of disease heritability. In addition, despite the substantial overlap of clinical and pathologic features among major neurodegenerative diseases, surprisingly few GWAS-implicated variants appear to exhibit cross-disease association. These realities suggest limitations of the focus on individual genetic variants and create challenges for the development of diagnostic and therapeutic strategies, which traditionally target an isolated molecule or mechanistic step. Recently, GWAS of complex diseases and traits have focused less on individual susceptibility variants and instead have emphasized the biological pathways and networks revealed by genetic associations. This new paradigm draws on the hypothesis that fundamental disease processes may be influenced on a personalized basis by a combination of variants - some common and others rare, some protective and others deleterious - in key genes and pathways. Here, we review and synthesize the major pathways implicated in neurodegeneration, focusing on GWAS from the most prevalent neurodegenerative disorders, AD and PD. Using literature mining, we also discover a novel regulatory network that is enriched with AD- and PD-associated genes and centered on the SP1 and AP-1 (Jun/Fos) transcription factors. Overall, this pathway- and network-driven model highlights several potential shared mechanisms in AD and PD that will inform future studies of these and other neurodegenerative disorders. These insights also suggest that biomarker and treatment strategies may require simultaneous targeting of multiple components, including some specific to disease stage, in order to assess and modulate neurodegeneration. Pathways and networks will provide ideal vehicles for integrating relevant findings from GWAS and other modalities to enhance clinical translation.
    American Journal of Neurodegenerative Diseases 10/2013; 2(3):145-175.
Show more


12 Reads
Available from