Novel targets for Huntington's disease in an mTOR-independent autophagy pathway

Williams, Andrea; Sarkar, Sovan; Cuddon, Paul A.; Ttofi, Evangelia K; Saiki, Sachio; Siddiqi, Farah H.; Jahreiss, Luca; Fleming, Angeleen; Pask, Dean C.; Goldsmith, Paul C.; O’Kane, Cahir J.; Floto, R. Andres; Rubinsztein, David C.

doi:10.1038/nchembio.79

Cited by 728 publications

(815 citation statements)

References 48 publications

Supporting

Mentioning

771

Contrasting

Unclassified

Order By: Relevance

“…An additional pathway for the induction of autophagy has been described, that is independent of mTOR and mediated through the inhibition of Inositol monophosphatase (IMPase) and the subsequent reduction in Inositol or inositol-3-phosphate (IP 3 ) levels 165 . Therapeutically, this inhibition can be achieved through the treatment with lithium or valproate and is beneficial in Drosophila and Zebrafish models of HD 165 ( Figure 5).…”

Section: Targeting the Pi3 Kinase And Beclin Pathwaymentioning

confidence: 99%

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Section: Supplementary Materialsmentioning

confidence: 99%

See 1 more Smart Citation

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

View full text Add to dashboard Cite

Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

show abstract

Section: Targeting the Pi3 Kinase And Beclin Pathwaymentioning

confidence: 99%

Section: Supplementary Materialsmentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

View full text Add to dashboard Cite

show abstract

“…This effect can be achieved pharmacologically with drugs such as lithium or L-690 330, which disrupt the metabolism of inositol by inhibiting inositol monophosphatase. Rubinsztein and coworkers [123] found that L-type Ca 2+ channel antagonists, the K + ATP channel opener, and G i signaling activators all induce autophagy. These drugs reveal a cyclical mTOR-independent pathway regulating autophagy, in which cAMP regulates IP3 levels, influencing calpain activity, which completes the cycle by cleaving and activating G sα , which in turn regulates cAMP levels.…”

Section: Inositol 145-trisphosphate (Ip 3 ) Receptormentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

View full text Add to dashboard Cite

Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

show abstract

“…The therapeutic relevance of the two identified compounds that induce autophagy has been verified using cell, fly and zebrafish models of Huntington's disease. 79 Lithium also stimulates a novel mTOR-independent pathway that regulates autophagy and promotes aggregate clearance in cells and in Drosophila models of Huntington's disease. 80 Finally, mutations that affect the dynein machinery impair autophagosome-lysosome fusion, leading to decreased autophagic clearance of aggregate-prone proteins and enhanced toxicity of the mutation that causes Huntington's disease in fly and mouse models.…”

Section: Autophagy and Neurodegenerative Conditionsmentioning

confidence: 99%

Autophagy and cell death in model organisms

2008

View full text Add to dashboard Cite

Autophagy evolved in unicellular eukaryotes as a means for surviving nutrient stress. During the course of evolution, as multicellular organisms developed specialized cell types and complex intracellular signalling networks, autophagy has been summoned to serve additional cellular functions. Numerous recent studies indicate that apart from its pro-survival role under nutrient limitation, autophagy also participates in cell death. However, the precise role of this catabolic process in dying cells is not fully understood. Although in certain situations autophagy has a protective function, in other types of cell death it actually contributes to cellular destruction. Simple model organisms ranging from the unicellular Saccharomyces cerevisiae to the soil amoeba Dictyostelium discoideum and the metazoans Caenorhabditis elegans and Drosophila melanogaster provide clearly defined cell death paradigms that can be used to dissect the involvement of autophagy in cell death, at the molecular level. In this review, we survey current research in simple organisms, linking autophagy to cell death and discuss the complex interplay between autophagy, cell survival and cell death. Autophagy is a self-degradation process that is essential for survival, differentiation, development, and homeostasis. There are at least three forms of autophagy -chaperonemediated autophagy, microautophagy, and macroautophagy -that differ with respect to their mechanisms, physiological functions and cargo specificity. In the best-studied form of autophagy, macroautophagy (herein referred to as autophagy), parts of the cytoplasm, long-lived proteins and intracellular organelles are sequestered within cytoplasmic double-membrane vesicles called autophagosomes or autophagic vacuoles. These characteristic vacuoles are finally delivered to lysosomes for bulk degradation (Figure 1).Autophagy was discovered in mammalian cells and has been extensively investigated in yeast. 1 These studies have identified many genes encoding proteins involved in autophagy (ATG proteins). 2 ATG proteins participate in the induction of autophagy, the formation, expansion and maturation of autophagosomes, and in the retrieval of autophagic proteins from mature autophagosomes. 3 Fusion processes occur through the t-and v-SNARE complexes, and other molecules, such as the Rab GTPases and components of the vacuolar protein-sorting (VPS) complex. Several protein kinases regulate autophagy, the best characterized being the mammalian target of rapamycin (mTOR), which negatively regulates the pathway. 4 Downstream of TOR kinase, numerous proteins encoded by ATG genes (more than 20 genes in yeast) are essential for the execution of autophagy. 5 The autophagic process is evolutionarily conserved and most yeast ATG genes have homologues in higher organisms (Table 1).Autophagy has also been linked to cell death pathways. Indeed, excess cytoplasmic vacuolation is the main feature of type II programmed cell death or autophagic cell death. Both protective and destructive contributions of autop...

show abstract

Novel targets for Huntington's disease in an mTOR-independent autophagy pathway

Cited by 728 publications

References 48 publications

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Overview of macroautophagy regulation in mammalian cells

Autophagy and cell death in model organisms

Contact Info

Product

Resources

About