scholarly journals Roco Proteins and the Parkinson’s Disease-Associated LRRK2

2018 ◽  
Vol 19 (12) ◽  
pp. 4074 ◽  
Author(s):  
Jingling Liao ◽  
Quyen Hoang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
G Proteins ◽  
Conformational Changes ◽  
Effector Proteins ◽  
Cellular Processes ◽  
Current State ◽  
Specific Effector ◽  
Unique Domain ◽  
Small G Proteins

Small G-proteins are structurally-conserved modules that function as molecular on-off switches. They function in many different cellular processes with differential specificity determined by the unique effector-binding surfaces, which undergo conformational changes during the switching action. These switches are typically standalone monomeric modules that form transient heterodimers with specific effector proteins in the ‘on’ state, and cycle to back to the monomeric conformation in the ‘off’ state. A new class of small G-proteins called “Roco” was discovered about a decade ago; this class is distinct from the typical G-proteins in several intriguing ways. Their switch module resides within a polypeptide chain of a large multi-domain protein, always adjacent to a unique domain called COR, and its effector kinase often resides within the same polypeptide. As such, the mechanisms of action of the Roco G-proteins are likely to differ from those of the typical G-proteins. Understanding these mechanisms is important because aberrant activity in the human Roco protein LRRK2 is associated with the pathogenesis of Parkinson’s disease. This review provides an update on the current state of our understanding of the Roco G-proteins and the prospects of targeting them for therapeutic purposes.

scholarly journals PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER–Mitochondria Contacts in Parkinson’s Disease

2020 ◽  
Vol 21 (5) ◽  
pp. 1772 ◽  
Author(s):  
Lucia Barazzuol ◽  
Flavia Giamogante ◽  
Marisa Brini ◽  
Tito Calì
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Phosphatase And Tensin Homolog ◽  
Cellular Processes ◽  
Selective Degradation ◽  
Contact Sites ◽  
Tensin Homolog

Endoplasmic reticulum (ER)–mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson’s disease, are two of the best characterized mitophagy players. They accumulate at ER–mitochondria contact sites and modulate organelles crosstalk. Alterations in ER–mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson’s disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER–mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy.

scholarly journals Small G proteins as key regulators of pancreatic digestive enzyme secretion

2009 ◽  
Vol 296 (3) ◽  
pp. E405-E414 ◽  
Author(s):  
John A. Williams ◽  
Xuequn Chen ◽  
Maria E. Sabbatini
Keyword(s):  
G Proteins ◽  
Secretory Granule ◽  
Secretory Pathway ◽  
Digestive Enzyme ◽  
Pancreatic Acinar Cells ◽  
Cellular Processes ◽  
Granule Membrane ◽  
Target Membrane ◽  
Rho Family ◽  
Small G Proteins

Small GTP-binding (G) proteins act as molecular switches to regulate a number of cellular processes, including vesicular transport. Emerging evidence indicates that small G proteins regulate a number of steps in the secretion of pancreatic acinar cells. Diverse small G proteins have been localized at discrete compartments along the secretory pathway and particularly on the secretory granule. Rab3D, Rab27B, and Rap1 are present on the granule membrane and play a role in the steps leading up to exocytosis. Whether the function of these G proteins is simply to ensure appropriate targeting or if they are involved as regulatory molecules is discussed. Most evidence suggests that Rab3D and Rab27B play a role in tethering the secretory granule to its target membrane. Other Rabs have been identified on the secretory granule that are associated with different steps in the secretory pathway. The Rho family small G proteins RhoA and Rac1 also regulate secretion through remodeling of the actin cytoskeleton. Possible mechanisms for regulation of these G proteins and their effector molecules are considered.

scholarly journals Optimizing Cognitive Training for the Treatment of Cognitive Dysfunction in Parkinson’s Disease: Current Limitations and Future Directions

2021 ◽  
Vol 13 ◽  
Author(s):  
Bianca Guglietti ◽  
David Hobbs ◽  
Lyndsey E. Collins-Praino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Dysfunction ◽  
Cognitive Training ◽  
Assistive Technologies ◽  
Motor Impairments ◽  
Future Directions ◽  
Cognitive Domains ◽  
Current State ◽  
Non Motor Symptoms

Cognitive dysfunction, primarily involving impairments in executive function, visuospatial function and memory, is one of the most common non-motor symptoms of Parkinson’s disease (PD). Currently, the only pharmacological treatments available for the treatment of cognitive dysfunction in PD provide variable benefit, making the search for potential non-pharmacological therapies to improve cognitive function of significant interest. One such therapeutic strategy may be cognitive training (CT), which involves the repetition of standardized tasks with the aim of improving specific aspects of cognition. Several studies have examined the effects of CT in individuals with PD and have shown benefits in a variety of cognitive domains, but the widespread use of CT in these individuals may be limited by motor impairments and other concerns in study design. Here, we discuss the current state of the literature on the use of CT for PD and propose recommendations for future implementation. We also explore the potential use of more recent integrative, adaptive and assistive technologies, such as virtual reality, which may optimize the delivery of CT in PD.

scholarly journals Functional Recovery in Parkinson’s Disease: Current State and Future Perspective

2020 ◽  
Vol 9 (11) ◽  
pp. 3413
Author(s):  
Manuela Violeta Bacanoiu ◽  
Radu Razvan Mititelu ◽  
Mircea Danoiu ◽  
Gabriela Olaru ◽  
Ana Maria Buga
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Search Strategy ◽  
Future Perspective ◽  
Sensory Cues ◽  
Rehabilitation Programs ◽  
Current State ◽  
Physical Exercises ◽  
Therapeutic Activities ◽  
The Impact

Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders, affecting not only the motor function but also limiting the autonomy of affected people. In the last decade, the physical exercises of different intensities carried out by kinetic therapeutic activities, by robotic technologies or with the participation of sensory cues, have become increasingly appreciated in the management of Parkinson’s disease impairments. The aim of this paper was to evaluate the impact of physical exercises with and without physical devices on the motor and cognitive variables of PD patients. In order to achieve our objectives, we performed a systematic review of available original articles based on the impact of kinetic therapeutic activity. Through the search strategy, we selected original papers that were laboriously processed using characteristics related to physical therapy, or the tools used in physiological and psychological rehabilitation strategies for PD patients. In this study, we presented the most current intervention techniques in the rehabilitation programs of patients with Parkinson’s disease, namely the use of assisted devices, virtual imagery or the performing of physical therapies that have the capacity to improve walking deficits, tremor and bradykinesia, to reduce freezing episodes of gait and postural instability, or to improve motor and cognitive functions.

scholarly journals The IQGAP1-Rac1 and IQGAP1-Cdc42 Interactions

2007 ◽  
Vol 283 (3) ◽  
pp. 1692-1704 ◽  
Author(s):  
Darerca Owen ◽  
Louise J. Campbell ◽  
Keily Littlefield ◽  
Katrina A. Evetts ◽  
Zhigang Li ◽  
...  
Keyword(s):  
G Proteins ◽  
Binding Sites ◽  
Effector Proteins ◽  
Total Binding Energy ◽  
Relative Importance ◽  
Gtpase Activating Proteins ◽  
Cold Spots ◽  
Rho Family ◽  
Binding Interfaces ◽  
Small G Proteins

IQGAP1 contains a domain related to the catalytic portion of the GTPase-activating proteins (GAPs) for the Ras small G proteins, yet it has no RasGAP activity and binds to the Rho family small G proteins Cdc42 and Rac1. It is thought that IQGAP1 is an effector of Rac1 and Cdc42, regulating cell-cell adhesion through the E-cadherin-catenin complex, which controls formation and maintenance of adherens junctions. This study investigates the binding interfaces of the Rac1-IQGAP1 and Cdc42-IQGAP1 complexes. We mutated Rac1 and Cdc42 and measured the effects of mutations on their affinity for IQGAP1. We have identified similarities and differences in the relative importance of residues used by Rac1 and Cdc42 to bind IQGAP1. Furthermore, the residues involved in the complexes formed with IQGAP1 differ from those formed with other effector proteins and GAPs. Relatively few mutations in switch I of Cdc42 or Rac1 affect IQGAP1 binding; only mutations in residues 32 and 36 significantly decrease affinity for IQGAP1. Switch II mutations also affect binding to IQGAP1 although the effects differ between Rac1 and Cdc42; mutation of either Asp-63, Arg-68, or Leu-70 abrogate Rac1 binding, whereas no switch II mutations affect Cdc42 binding to IQGAP1. The Rho family “insert loop” does not contribute to the binding affinity of Rac1/Cdc42 for IQGAP1. We also present thermodynamic data pertaining to the Rac1/Cdc42-RhoGAP complexes. Switch II contributes a large portion of the total binding energy to these complexes, whereas switch I mutations also affect binding. In addition we identify “cold spots” in the Rac1/Cdc42-RhoGAP/IQGAP1 interfaces. Competition data reveal that the binding sites for IQGAP1 and RhoGAP on the small G proteins overlap only partially. Overall, the data presented here suggest that, despite their 71% identity, Cdc42 and Rac1 appear to have only partially overlapping binding sites on IQGAP1, and each uses different determinants to achieve high affinity binding.

scholarly journals Rho GTPases and their effector proteins

2000 ◽  
Vol 348 (2) ◽  
pp. 241-255 ◽  
Author(s):  
Anne L. BISHOP ◽  
Alan HALL
Keyword(s):  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Biological Effects ◽  
Effector Proteins ◽  
Actin Dynamics ◽  
Filamentous Actin ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Specific Effector ◽  
Rho Family

Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

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