Journal: Brain

Article Title: Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism

doi: 10.1093/brain/awv371

Figure Lengend Snippet: Macroautophagy: an overview of the molecular pathway and mutations associated with congenital disorders of autophagy. Macroautophagy is a step-wise process resulting in the formation of double-membrane-bound autophagic vesicles that engulf their cargo before fusing with lysosomes. The principle stages of macroautophagy include: (I) initiation; (II) nucleation of an isolation membrane (also called phagophore); (III) elongation of evolving autophagic vesicles; (IV) engulfment of cargo and closure of the autophagosomal membrane; (V) autophagosome maturation; (VI) fusion with late endosomes or lysosomes; and finally (VII) degradation of cargo through lysosomal hydrolases. The last step yields basic metabolites that are then recycled. Mutations in congenital disorders of autophagy and single gene disorders associated with deficits in the regulation of autophagy impair different stages of the pathway. Through interfering with the beclin 1 complex, hereditary spastic paraplegia-associated recessive mutations in ZFYVE26 (SPG15) impair early stages such as the formation of the isolation membrane. Mutations in TECPR2 (SPG49) were recently shown to be critically involved in maintaining endoplasmic reticulum exit sites that may serve as scaffolds for the formation of early autophagosome intermediates. X-linked WDR45 mutations cause beta-propeller protein-associated neurodegeneration (BPAN) and have been found to potentially interfere with the elongation of nascent autophagic vesicles. Autosomal-recessive EPG5 mutations in Vici syndrome as well as SNX14 mutations in SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome impact the late stages of the autophagy pathway through impairing autophagosome-lysosome fusion. Mutations in SPG11 (SPG11) lead to a defect in autophagic lysosome reformation. Autophagy-associated diseases also affect different stages of autophagy regulation. An example for mTOR-associated neurodevelopmental diseases, loss-of-function mutations in TSC1 or TSC2 in tuberous sclerosis complex lead to constitutive activation of mTORC1 and thus block autophagic flux at multiple stages. Locating the defect to the late stages of the pathway, lysosomal storage diseases impact lysosomal metabolism and thus block upstream steps in the autophagy pathway. Impaired crosstalk between the lysosomal pathway and autophagosome biogenesis might also impact the coordinated regulation of both compartments. AR-CAID = autosomal-recessive cerebellar ataxia and intellectual disability syndrome; LSD = lysosomal storage disease; TSC = tuberous sclerosis complex.

Article Snippet: Overactive mTORC1 is the key pathogenic molecular mechanism in TSC and provides the scientific rationale for the use of mTORC1 inhibitors to treat this disease ( Julich and Sahin, 2014 ; Ebrahimi-Fakhari and Sahin, 2015 ).

Techniques: Membrane, Isolation, Activation Assay, Blocking Assay

Journal: Brain

Article Title: Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism

doi: 10.1093/brain/awv371

Figure Lengend Snippet: Modulators of autophagy in neuronal disease models

Article Snippet: Overactive mTORC1 is the key pathogenic molecular mechanism in TSC and provides the scientific rationale for the use of mTORC1 inhibitors to treat this disease ( Julich and Sahin, 2014 ; Ebrahimi-Fakhari and Sahin, 2015 ).

Techniques: Inhibition, Activation Assay

Journal: BMC Bioinformatics

Article Title: Overview of the Cancer Genetics and Pathway Curation tasks of BioNLP Shared Task 2013

doi: 10.1186/1471-2105-16-S10-S2

Figure Lengend Snippet: Pathway models used to select documents for the Pathway Curation task.

Article Snippet: mTORC1 upstream regulators , BioModels , MODEL1012220003 , [ ] .

Techniques:

Journal: The Journal of Physiology

Article Title: Placental phenotype and the insulin‐like growth factors: resource allocation to fetal growth

doi: 10.1113/JP273330

Figure Lengend Snippet: The effect of maternal environmental challenge on fetal growth and placental structure, function and IGF signalling

Article Snippet: 13% , Mouse , D1 to 19 , D19 ↑ Insulin‐IGF (↑ pAKT) and mTORC1 signalling , D19 ↑10% , D19 ↑ Maternal arterial and venous blood space , ND , D19 ↓ 12% weight and litter size , Matheson et al . ( 2015 );.

Techniques: Activity Assay, Disruption, Ligation, Phospho-proteomics, Diffusion-based Assay

Journal: Glia

Article Title: Myelination and mTOR

doi: 10.1002/glia.23273

Figure Lengend Snippet: mTORC1 and its upstream pathways. A schematic representation of the main components of the mTORC1 pathway and major upstream pathways controlling mTORC1 activity is shown. The red line highlights the major inhibitory feedback loop from mTORC1 to PI3K‐Akt

Article Snippet: How are mTORC1 activity levels in remyelinating cells affecting repair after lesions (McLane et al., )?

Techniques: Activity Assay

Journal: Glia

Article Title: Myelination and mTOR

doi: 10.1002/glia.23273

Figure Lengend Snippet: Molecular events downstream of mTORC1 during cell differentiation and myelin growth. Before onset of myelination, mTORC1 controls differentiation of myelinating cells. In the PNS, it suppresses transiently Krox20 expression via S6K and thus the transition from promyelinating to myelinating SCs. A decline in mTORC1 activity releases this block and allows myelination to proceed. In the CNS, mTORC1 activity promotes differentiation of OLs from OPCs through unknown mechanisms. After onset of myelination, mTORC1 positively regulates myelin production in both the PNS and CNS. In the PNS, mTORC1 signaling increases expression of SREBP1c via the transcription factor RXRγ, while probably promoting SREBP2 activation through post‐translational mechanisms. In the CNS, mTORC1 positively regulates at the transcriptional level expression of SREBP2, but not SREBP1c. Additionally, mTORC1 signaling stimulates translation of MBP. How mTORC1 activity changes during development of SCs with respect to Krox20 levels is graphically indicated in the bottom part of the figure. No analogous information is yet available for OL‐lineage cell development. Dashed lines indicate indirect and/or in detail unknown mechanisms

Article Snippet: How are mTORC1 activity levels in remyelinating cells affecting repair after lesions (McLane et al., )?

Techniques: Cell Differentiation, Expressing, Activity Assay, Blocking Assay, Activation Assay

Journal: Glia

Article Title: Myelination and mTOR

doi: 10.1002/glia.23273

Figure Lengend Snippet: Potential perturbation of mTORC1‐independent targets upon disruption of the TSC complex. Due to feedback inhibition of the upstream pathways, hyperactivation of mTORC1 after disruption of the TSC complex (on the right) has the potential to perturb also mTORC1‐independent targets of Akt and Erk1/2 (“other targets”) leading to different outcomes (symbolized by differently colored arrows). A similar general mechanism appears to underlie paradoxical effects of TSC1 or TSC2 deletion in other cell types. The green halo indicates level of activity. Note that phosphorylation of mTORC1‐independent targets by Akt or Erk1/2 may be either activating or inhibitory

Article Snippet: How are mTORC1 activity levels in remyelinating cells affecting repair after lesions (McLane et al., )?

Techniques: Disruption, Inhibition, Activity Assay, Phospho-proteomics

Journal: Glia

Article Title: Myelination and mTOR

doi: 10.1002/glia.23273

Figure Lengend Snippet: Overview of the outcomes of loss‐ or gain‐of‐function studies of various components of mTORC1 and upstream pathways. The major outcomes of the loss‐ and gain‐of‐function studies on the roles of mTORC1 and the upstream PI3K‐Akt and Mek‐Erk1/2 pathways in PNS and CNS myelination are summarized (Beirowski et al., ; Bercury et al., ; Carson et al., ; Cotter et al., ; Domenech‐Estevez et al., ; Figlia et al., ; Flores et al., ; Fyffe‐Maricich, Karlo, Landreth, & Miller, ; Fyffe‐Maricich, Schott, Karl, Krasno, & Miller, ; Goebbels et al., , ; Ishii, Furusho, & Bansal, ; Ishii, Furusho, Dupree, & Bansal, ; Jeffries et al., ; Jiang et al., ; Lebrun‐Julien et al., ; Napoli et al., ; Newbern et al., ; Norrmén et al., ; Sheean et al., ; Sherman et al., ; Wahl et al., ; Zou et al., , )

Article Snippet: How are mTORC1 activity levels in remyelinating cells affecting repair after lesions (McLane et al., )?

Techniques: