Tau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo
ABSTRACT 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.
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Article: What Renders TAU Toxic[Show abstract] [Hide abstract]
ABSTRACT: TAU is a microtubule-associated protein that under pathological conditions such as Alzheimer's disease (AD) forms insoluble, filamentous aggregates. When 20 years after TAU's discovery the first TAU transgenic mouse models were established, one declared goal that was achieved was the modeling of authentic TAU aggregate formation in the form of neurofibrillary tangles. However, as we review here, it has become increasingly clear that TAU causes damage much before these filamentous aggregates develop. In fact, because TAU is a scaffolding protein, increased levels and an altered subcellular localization (due to an increased insolubility and impaired clearance) result in the interaction of TAU with cellular proteins with which it would otherwise either not interact or do so to a lesser degree, thereby impairing their physiological functions. We specifically discuss the non-axonal localization of TAU, the role phosphorylation has in TAU toxicity and how TAU impairs mitochondrial functions. A major emphasis is on what we have learned from the four available TAU knock-out models in mice, and the knock-out of the TAU/MAP2 homolog PTL-1 in worms. It has been proposed that in human pathological conditions such as AD, a rare toxic TAU species exists which needs to be specifically removed to abrogate TAU's toxicity and restore neuronal functions. However, what is toxic in one context may not be in another, and simply reducing, but not fully abolishing TAU levels may be sufficient to abrogate TAU toxicity.Frontiers in Neurology 06/2013; 4:72. DOI:10.3389/fneur.2013.00072
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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.01/2013; 2(3):145-175.
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ABSTRACT: The worldwide incidence of Alzheimer's disease (AD) is increasing with estimates that 115 million individuals will have AD by 2050, creating an unsustainable healthcare challenge due to a lack of effective treatment options highlighted by multiple clinical failures of agents designed to reduce the brain amyloid burden associated with AD. The amyloid hypothesis that has been the overarching focus of AD research efforts for more than two decades has been questioned in terms of its causality but has not been unequivocally disproven despite multiple clinical failures, This is due to issues related to the quality of compounds advanced to late stage clinical trials and the lack of validated biomarkers that allow the recruitment of AD patients into trials before they are at a sufficiently advanced stage in the disease where therapeutic intervention is deemed futile. Pursuit of a linear, reductionistic amyloidocentric approach to AD research, which some have compared to a religious faith, has resulted in other, equally plausible but as yet to be validated AD hypotheses being underfunded leading to a disastrous roadblock in the search for urgently needed AD therapeutics. Genetic evidence supporting amyloid causality in AD is reviewed in the context of the clinical failures, progress in tau-based and alternative approaches to AD, where an evolving modus operandi in biomedical research fosters excessive optimism and a preoccupation with unproven, and often ephemeral, biomarker/genome-based approaches that override transparency, objectivity and data-driven decision making, resulting in low probability environments where data are subordinate to self propagating hypotheses.Biochemical pharmacology 11/2012; 85(3). DOI:10.1016/j.bcp.2012.11.014 · 4.65 Impact Factor