RasGRP1 is a causal factor in the development of
            <scp>l</scp>
            -DOPA–induced dyskinesia in Parkinson’s disease

Eshraghi, Mehdi; Ramírez-Jarquín, Uri Nimrod; Shahani, Neelam; Nuzzo, Tommaso; Rosa, Arianna De; Swarnkar, Supriya; Galli, Nicole; Rivera, Oscar; Tsaprailis, George; Scharager-Tapia, Catherina; Crynen, Gogce; Li, Qin; Thiolat, Marie-Laure; Bézard, Erwan; Usiello, Alessandro; Subramaniam, Srinivasa

doi:10.1126/sciadv.aaz7001

Cited by 35 publications

(35 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, l -DOPA-treated RasGRP1 -/- mice do not display dyskinesia [ 28 ]. Moreover, l -DOPA promotes the activation of extracellular signal-regulated kinase (ERK) and mTORC1 [ 29 ]. As RasGRP1 acts as a GEF for both Ras and Rheb (another Ras family GTPase), the authors suggested that in the presence of l -DOPA, RasGRP1 could form complexes with both GTPases.…”

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

“…As RasGRP1 acts as a GEF for both Ras and Rheb (another Ras family GTPase), the authors suggested that in the presence of l -DOPA, RasGRP1 could form complexes with both GTPases. On one hand, it could associate with H-Ras to initiate ERK signaling; on the other hand, it could activate Rheb to signal via mTOR [ 29 ]. Hence, parallel activation of these two cascades could provoke the onset and progression of L-DOPA-induced dyskinesia [ 29 ].…”

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

“…On one hand, it could associate with H-Ras to initiate ERK signaling; on the other hand, it could activate Rheb to signal via mTOR [ 29 ]. Hence, parallel activation of these two cascades could provoke the onset and progression of L-DOPA-induced dyskinesia [ 29 ].…”

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

“…Because this phosphorylation resulted in GAP inhibition and consequent Rheb activation, this study suggested that this mechanism could trigger neuronal death in various neurodegenerative pathologies such as AD and/or PD [ 65 ]. Moreover, as previously explained, simultaneous signaling by the RasGRP1/Rheb/mTORC1 and RasGRP1/H-Ras/ERK axes could underlie the dyskinesia suffered by PD patients who have been treated with L-DOPA for a prolonged time [ 29 ]. mTOR has also been shown to induce Tau phosphorylation and its pharmacological inhibition alleviated the pathology and the behavior deficits in human Tau overexpressing mice.…”

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

See 3 more Smart Citations

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Sastre

Montoro

Gálvez‐Martín

et al. 2020

IJMS

View full text Add to dashboard Cite

Small guanosine triphosphatases (GTPases) of the Ras superfamily are key regulators of many key cellular events such as proliferation, differentiation, cell cycle regulation, migration, or apoptosis. To control these biological responses, GTPases activity is regulated by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in some small GTPases also guanine nucleotide dissociation inhibitors (GDIs). Moreover, small GTPases transduce signals by their downstream effector molecules. Many studies demonstrate that small GTPases of the Ras family are involved in neurodegeneration processes. Here, in this review, we focus on the signaling pathways controlled by these small protein superfamilies that culminate in neurodegenerative pathologies, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Specifically, we concentrate on the two most studied families of the Ras superfamily: the Ras and Rho families. We summarize the latest findings of small GTPases of the Ras and Rho families in neurodegeneration in order to highlight these small proteins as potential therapeutic targets capable of slowing down different neurodegenerative diseases.

show abstract

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

Section: Small Gtpases Of the Ras Familymentioning

confidence: 99%

See 2 more Smart Citations

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Sastre

Montoro

Gálvez‐Martín

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…pGEX6p2-GST-GβL was cloned from pRK5-HA-GβL into pGEX6p2-GST and was transformed into BL21 (DE3) cells (New England Biolabs) and purified using Glutathione Sepharose beads (45000139, Fisher) as described in our previous studies [34,35,65,67].…”

Section: In Vitro Sumoylationmentioning

confidence: 99%

SUMO Modifies GβL and Mediates mTOR Signaling

Park

Ramírez-Jarquín

Shahani

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The mechanistic target of rapamycin (mTOR) signaling is influenced by multiple regulatory proteins and post-translational modifications, however, underlying mechanisms remains unclear. Here, we report a novel role of small ubiquitin-like modifier (SUMO) in mTOR complex assembly and activity. By investigating the SUMOylation status of core mTOR components, we observed that the regulatory subunit, GβL, is modified by SUMO1, 2, and 3 isoforms. Using mutagenesis and mass spectrometry, we identified that GβL is SUMOylated at lysine sites K86, K215, K245, K261 and K305. We found that SUMO depletion reduces mTOR-Raptor and mTOR-Rictor complex formation and diminishes nutrient-induced mTOR signaling. Furthermore, we found that reconstitution with WT GβL but not SUMOylation defective KR mutant GβL promote mTOR signaling in GβL-depleted cells. Taken together, we report for the very first time that SUMO modifies GβL, influences the assembly of mTOR protein complexes, and regulates mTOR activity.

show abstract

Rhes, a striatal enriched protein, regulates post-translational small-ubiquitin-like-modifier (SUMO) modification of nuclear proteins and alters gene expression

Rivera,

Sharma,

Dagar

et al. 2024

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPase family member which contains a unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain that promotes SUMO post-translational modification of proteins (SUMOylation) by promoting “cross-SUMOylation” of the SUMO enzyme SUMO E1 (Aos1/Uba2) and SUMO E2 ligase (Ubc-9). Nevertheless, the identity of the SUMO substrates of Rhes remains largely unknown. Here, by combining high throughput interactome and SUMO proteomics, we report that Rhes regulates the SUMOylation of nuclear proteins that are involved in the regulation of gene expression. Rhes increased the SUMOylation of histone deacetylase 1 (HDAC1) and histone 2B, while decreasing SUMOylation of heterogeneous nuclear ribonucleoprotein M (HNRNPM), protein polybromo-1 (PBRM1) and E3 SUMO-protein ligase (PIASy). We also found that Rhes itself is SUMOylated at 6 different lysine residues (K32, K110, K114, K120, K124, and K245). Furthermore, Rhes regulated the expression of genes involved in cellular morphogenesis and differentiation in the striatum, in a SUMO-dependent manner. Our findings thus provide evidence for a previously undescribed role for Rhes in regulating the SUMOylation of nuclear targets and in orchestrating striatal gene expression via SUMOylation.

show abstract

RasGRP1 is a causal factor in the development of l -DOPA–induced dyskinesia in Parkinson’s disease

Cited by 35 publications

References 42 publications

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

SUMO Modifies GβL and Mediates mTOR Signaling

Rhes, a striatal enriched protein, regulates post-translational small-ubiquitin-like-modifier (SUMO) modification of nuclear proteins and alters gene expression

Contact Info

Product

Resources

About