Multiple roles for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) have been recently appreciated. In addition to the cytoplasm where majority of GAPDH is located under the basal condition, GAPDH is also found in the particulate fractions, such as the nucleus, the mitochondria, and the small vesicular fractions. When cells are exposed to various stressors, dynamic subcellular re-distribution of GAPDH occurs. Here we review these multifunctional properties of GAPDH, especially linking them to its oligomerization, posttranslational modification, and subcellular localization. This includes mechanistic descriptions of how S-nitrosylation of GAPDH under oxidative stress may lead to cell death/dysfunction via nuclear translocation of GAPDH, which is counteracted by a cytosolic GOSPEL. GAPDH is also involved in various diseases, especially neurodegenerative disorders and cancers. Therapeutic strategies to these conditions based on molecular understanding of GAPDH are discussed.

Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade 1-9 . Diverse apoptotic stimuli activate inducible nitric oxide synthase (iNOS) or neuronal NOS (nNOS), with the generated nitric oxide (NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (refs 10 -15 ), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.10Correspondence and requests for materials should be addressed A.S. or S.H.S (E-mail: asawa1@jhmi.edu; E-mail: ssnyder@jhmi.edu). 8 Current address: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. 9 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS Ni.S. and M.R.H. were primarily responsible for experimental design and work, data analysis and preparation of figures, and helped to write the manuscript; M.K., M.C., B.-I.B., Ne.S. and B.T. contributed to data acquisition and analysis; T.D. and V.D. helped with the data analysis, provided technical assistance and material support; S.H.S and A.S. supervised the project and wrote the manuscript.Note: Supplementary Information is available on the Nature Cell Biology website. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. -(3-(aminomethyl)benzyl)acetamidine (1400W), a selective iNOS inhibitor (Fig. 1a). To ascertain whether p300 and/or CBP are physiologically responsible for GAPDH acetylation in intact cells, we depleted p300 and CBP by RNA interference (RNAi). Depletion of either protein decreased GAPDH acetylation, which was abolished following depletion of both CBP and p300 (Fig. 1b). We also observed acetylation of GAPDH by p300 in vitro ( Supplementary Information, Fig. S1a). Moreover, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometric analysis of nuclear GAPDH in HEK293 cells following apoptotic stress revealed acetylation at Lys 160 ( Supplementary Information, Fig. S1b, c). To confirm the site of acetylation in intact cells, we transfected HEK293 cells with GAPDH or a mutant GAPDH (GAPDH-K160R). We observed acetylation of wild-type but not the K160R mutant GAPDH (Fi...

Tau becomes characteristically altered both functionally and structurally in several neurodegenerative diseases now collectively called tauopathies. Although increasing evidence supports that alterations of tau may directly cause neuronal degeneration and cell death, the mechanisms, which render tau to become a toxic agent are still unclear. In addition, it is obscure, whether neurodegeneration in tauopathies occurs via a common mechanism or specific differences exist. The aim of this review is to provide an overview about the different experimental models that currently exist, how they are used to determine the role of tau during degeneration and what has been learnt from them concerning the mechanistic role of tau in the disease process. The review begins with a discussion about similarities and differences in tau alteration in paradigmatic tauopathies such as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). The second part concentrates on major experimental models that have been used to address the mechanistic role of tau during degeneration. This will include a discussion of cell-free assays, culture models using cell lines or dissociated neurons, and animal models. How these models aid to understand (i) alterations in the function of tau as a microtubule-associated protein (MAP), (ii) direct cytotoxicity of altered tau protein, and (iii) the potential role of tau aggregation in neurodegenerative processes will be the central theme of this part. The review ends with concluding remarks about a general mechanistic model of the role of tau alteration and neuronal degeneration in tauopathies and future perspectives.

L–DOPA–induced dyskinesia, the rate–limiting side–effect in the therapy of Parkinson’s Disease, is mediated by activation of mTOR signaling in the striatum. We show that Rhes, a striatal–specific protein, binds to and activates mTOR. Moreover, Rhes deleted mice manifest reduced striatal mTOR signaling and diminished dyskinesia but maintain motor improvement upon L–DOPA treatment, implying therapeutic benefit for Rhes–binding drugs.

Background:The striatal-specific protein Rhes is implicated in the selective pathology of HD. Results: Rhes binds Beclin-1 and activates autophagy, a lysosomal degradation pathway critical in aging and neurodegeneration. Conclusion: Rhes-induced autophagy occurs independent of mTOR and JNK-1 signaling and is inhibited by huntingtin. Significance: The restricted expression of Rhes and its effect on autophagy may explain the selective striatal pathology and delayed onset of HD.

The tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play major regulatory roles in the organization and integrity of the cytoskeleton network. Neurofibrillary changes of abnormally hyperphosphorylated tau are a key lesion in Alzheimer's disease and a number of other tauopathies. However, despite an ever-increasing body of data on the changes which tau undergoes in disease, its role regarding the fundamental disease process is still unclear. Moreover, conceptions of tau functions continue to evolve, which complicates an understanding of its role in the disease process. This review attempts to summarize data on the role of tau proteins in the context of both normal cellular function and dysfunction. Furthermore, we try to develop a mechanistic framework for the involvement of tau during the disease process. The review closes with a look towards various approaches to elucidate the functions and malfunctions of tau.

In patients with Huntington's disease (HD), the protein huntingtin (Htt) has an expanded polyglutamine (poly-Q) tract. HD results in early loss of medium spiny neurons in the striatum, which impairs motor and cognitive functions. Identifying the physiological role and molecular functions of Htt may yield insight into HD pathogenesis. We found that Htt promotes signaling by mTORC1 [mechanistic target of rapamycin (mTOR) complex 1] and that this signaling is potentiated by poly-Q-expanded Htt. Knocking out Htt in mouse embryonic stem cells or human embryonic kidney cells attenuated amino acid-induced mTORC1 activity, whereas overexpressing wild-type or poly-Q-expanded Htt in striatal neuronal cells increased basal mTOR activity. Striatal cells expressing endogenous poly-Q-expanded Htt showed an increase in the number and size of mTOR puncta on the perinuclear regions compared to cells expressing wild-type Htt. Pull-down experiments indicated that amino acids stimulated the interaction of Htt and the guanosine triphosphatase (GTPase) Rheb (a protein that stimulates mTOR activity), and that Htt forms a ternary complex with Rheb and mTOR. Pharmacologically inhibiting PI3K (phosphatidylinositol 3-kinase) or knocking down Rheb abrogated mTORC1 activity induced by expression of a poly-Q-expanded amino-terminal Htt fragment. Moreover, striatum-specific deletion of TSC1, encoding tuberous sclerosis 1, a negative regulator of mTORC1, accelerated the onset of motor coordination abnormalities and caused premature death in an HD mouse model. Together, our findings demonstrate that mutant Htt contributes to the pathogenesis of HD by enhancing mTORC1 activity.

Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations of amyloid ␤, and intracellular fibrils containing hyperphosphorylated tau. Tau mutations in familial tauopathies confirmed a central role of tau pathology; however, the role of tau alteration and the sequence of tau-dependent neurodegeneration in AD remain elusive. Using Sindbis virus-mediated expression of AD-relevant tau constructs in hippocampal slices, we show that disease-like tau modifications affect tau phosphorylation at selected sites, induce Alz50/MC1-reactive pathological tau conformation, cause accumulation of insoluble tau, and induce region-specific neurodegeneration. Live imaging demonstrates that tau-dependent degeneration is associated with the development of a "ballooned" phenotype, a distinct feature of cell death. Spine density and morphology is not altered as judged from algorithmbased evaluation of dendritic spines, suggesting that synaptic integrity is remarkably stable against tau-dependent degeneration. The data provide evidence that tau-induced cell death involves apoptotic as well as nonapoptotic mechanisms. Furthermore, they demonstrate that targeted expression of tau in hippocampal slices provides a novel model to analyze tau modification and spatiotemporal dynamics of tau-dependent neurodegeneration in an authentic CNS environment.