Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation

Shahani, Neelam; Pryor, William M.; Swarnkar, Supriya; Kholodilov, Nikolai; Wang, Shuai; Burke, Robert E.; Subramaniam, Srinivasa

doi:10.1074/jbc.m113.532713

Cited by 51 publications

(55 citation statements)

References 54 publications

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“…In addition, using LC-MS E we detected a changed expression of proteins of the GTPase Rab protein family (e.g., RAB37, RAB35 and RAB3B, of which Rab37 was validated by Western blot) that are also involved in vesicle formation and docking [18,19]. Although there are no data to indicate an interaction of DISC1 with members of the Rab family or other significantly changed proteins involved in cellular transport such as pleckstrin homology domain-containing family A member 8 (PKHA8) and transmembrane protein 106B (T106B), DISC1 has been implicated in mitochondrial trafficking [20,21,22]. These findings point to potentially new DISC1 partners and mechanisms whereby DISC1 might be involved in neuronal transport.…”

Section: Discussionmentioning

confidence: 99%

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

et al. 2016

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Despite the recent progress in psychiatric genetics, very few studies have focused on genetic risk factors in glial cells that, compared to neurons, can manifest different molecular pathologies underlying psychiatric disorders. In order to address this issue, we studied the effects of mutant disrupted in schizophrenia 1 (DISC1), a genetic risk factor for schizophrenia, in cultured primary neurons and astrocytes using an unbiased mass spectrometry-based proteomic approach. We found that selective expression of mutant DISC1 in neurons affects a wide variety of proteins predominantly involved in neuronal development (e.g., SOX1) and vesicular transport (Rab proteins), whereas selective expression of mutant DISC1 in astrocytes produces changes in the levels of mitochondrial (GDPM), nuclear (TMM43) and cell adhesion (ECM2) proteins. The present study demonstrates that DISC1 variants can perturb distinct molecular pathways in a cell type-specific fashion to contribute to psychiatric disorders through heterogenic effects in diverse brain cells.

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Section: Discussionmentioning

confidence: 99%

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

et al. 2016

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“…Images were analyzed for the number and size of mTOR puncta using Fiji software, as described previously (78). Where indicated, Pearson's r colocalization threshold was calculated using Fiji software.…”

Section: Immunostainingmentioning

confidence: 99%

Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease

et al. 2014

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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.

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“…The authors suggest that PLD1 is an effector of Rheb. Rheb was also reported to interact with BACE1 (β-secretase) in mouse brain, suggesting that Rheb is a new physiological regulator of BACE1 (β-secretase) and amyloid-β generation [75]. BACE1 initiates processing of the amyloid precursor protein to generate amyloid-β, a hallmark event of Alzheimer’s disease (AD).…”

Section: Mtorc1-dependent and Independent Functions Of Rhebmentioning

confidence: 99%

Recent progress in the study of the Rheb family GTPases

Heard

Fong

Bathaie

et al. 2014

Cellular Signalling

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In this review we highlight recent progress in the study of Rheb family GTPases. Structural studies using X-ray crystallography and NMR have given us insight into unique features of this GTPase. Combined with mutagenesis studies, these works have expanded our understanding of residues that affect Rheb GTP/GDP bound ratios, effector protein interactions, and stimulation of mTORC1 signaling. Analysis of cancer genome databases has revealed that several human carcinomas contain activating mutations of the protein. Rheb’s role in activating mTORC1 signaling at the lysosome in response to stimuli has been further elucidated. Rheb has also been suggested to play roles in other cellular pathways including mitophagy and peroxisomal ROS response. A number of studies in mice have demonstrated the importance of Rheb in development, as well as in a variety of functions including cardiac protection and myelination. We conclude with a discussion of future prospects in the study of Rheb family GTPases.

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Rheb GTPase Regulates β-Secretase Levels and Amyloid β Generation

Cited by 51 publications

References 54 publications

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington’s disease

Recent progress in the study of the Rheb family GTPases

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