Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

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.

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“…In vivo, CNF1 treatment in 6-OHDA-treated mice improved motor asymmetries. Thus, Rho GTPases display a neurorestorative potential for PD [ 108 ].…”

Section: Small Gtpases Of the Rho Familymentioning

confidence: 99%

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

Sastre

Montoro

Gálvez‐Martín

et al. 2020

IJMS

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“…In a recent work, Musilli et al targeted cerebral Rho GTPases in a rat model of PD obtained by unilateral injection of 6-hydroxydopamine (6-OHDA) in the striatum [2]. Rho GTPases are a class of regulatory proteins encompassing Rho, Rac and Cdc42 subfamilies that govern cell morphology and act as effectors of neurotrophic factors [3].…”

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confidence: 99%

A neurorestorative approach to Parkinson's disease

2017

Self Cite

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“…1,2 Conversely, the same CNF1-induced mechanisms that seem to trigger the harmful effects of these diseases (i.e., Rho GTPases activation, wide cellular actin reorganization and alteration of mitochondria homeostasis) have been exploited to relieve the symptoms of other severe neurological diseases. [14][15][16][17][18][19][20][21][22] As a result, there is a great attention for an inclusive study of this protein at the molecular level to decipher both its action as a toxin and as a potential drug. At this point, we think that the level of detail devoted to the structural characterization of the catalytic domain of the protein should be extended to the full-length CNF1.…”

Section: Discussionmentioning

confidence: 99%

“…The main effects of this process include the activation of a controlled immune response in the host and a wide reorganization of the actin cytoskeleton of the infected cell which is exploited for the bacterial uptake . CNF1 capability to directly affect Rho GTPases action and indirectly actin assembly and cellular bioenergetics has recently been exploited in the treatment of some severe neurological diseases, including Alzheimer's disease, Parkinson's disease and Rett syndrome …”

Section: Introductionmentioning

confidence: 99%

“…12,13 CNF1 capability to directly affect Rho GTPases action and indirectly actin assembly and cellular bioenergetics has recently been exploited in the treatment of some severe neurological diseases, including Alzheimer's disease, Parkinson's disease and Rett syndrome. [14][15][16][17][18][19][20][21][22] Several studies have pointed out the general structuration of CNF1 as an AB toxin, presenting two different receptorrecognition sites (an N-terminal 37LRP/67LR binding domain and a C-terminal Lu/BCAM binding domain) and a C-terminal catalytic domain catalyzing Rho deamidation. [23][24][25][26][27][28] The mechanism of internalization of this toxin is quite complex and requires its binding with both receptors, its transport via endocytosis and the release of the cleaved C-terminal domain in the cytosol after an acidic-dependent insertion of two hydrophobic regions in the endosomal membrane.…”

Section: Introductionmentioning

confidence: 99%

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High yield purification and first structural characterization of the full‐length bacterial toxin CNF1

Colarusso

Caterino

Fabbri

et al. 2017

Biotechnology Progress

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The Cytotoxic Necrotizing Factor 1 (CNF1) is a bacterial toxin secreted by certain Escherichia coli strains causing severe pathologies, making it a protein of pivotal interest in toxicology. In parallel, the CNF1 capability to influence important neuronal processes, like neuronal arborization, astrocytic support, and efficient ATP production, has been efficiently used in the treatment of neurological diseases, making it a promising candidate for therapy. Nonetheless, there are still some unsolved issues about the CNF1 mechanism of action and structuration probably caused by the difficulty to achieve sufficient amounts of the full-length protein for further studies. Here, we propose an efficient strategy for the production and purification of this toxin as a his-tagged recombinant protein from E. coli extracts (CNF1-H8). CNF1-H8 was expressed at the low temperature of 15°C to diminish its characteristic degradation. Then, its purification was achieved using an immobilized metal affinity chromatography (IMAC) and a size exclusion chromatography so as to collect up to 8 mg of protein per liter of culture in a highly pure form. Routine dynamic light scattering (DLS) experiments showed that the recombinant protein preparations were homogeneous and preserved this state for a long time. Furthermore, CNF1-H8 functionality was confirmed by testing its activity on purified RhoA and on HEp-2 cultured cells. Finally, a first structural characterization of the full-length toxin in terms of secondary structure and thermal stability was performed by circular dichroism (CD). These studies demonstrate that our system can be used to produce high quantities of pure recombinant protein for a detailed structural analysis. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:150-159, 2018.

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Therapeutic effects of the Rho GTPase modulator CNF1 in a model of Parkinson’s disease

Cited by 22 publications

References 53 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

A neurorestorative approach to Parkinson's disease

High yield purification and first structural characterization of the full‐length bacterial toxin CNF1

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