Author: Iqra NazishPublisher:
ISBN:
Category :
Languages : en
Pages :
Book Description
Investigating Leucine-rich Repeat Kinase 2 (LRRK2) Function
Author: Iqra NazishLeucine-Rich Repeat Kinase 2 (LRRK2)
Author: Hardy J. RideoutPublisher: Springer
ISBN: 3319499696
Category : Medical
Languages : en
Pages : 280
Book Description
This is the first book to assemble the leading researchers in the field of LRRK2 biology and neurology and provide a snapshot of the current state of knowledge, encompassing all major aspects of its function and dysfunction. The contributors are experts in cell biology and physiology, neurobiology, and medicinal chemistry, bringing a multidisciplinary perspective on the gene and its role in disease. The book covers the identification of LRRK2 as a major contributor to the pathogenesis of Parkinson's Disease. It also discusses the current state of the field after a decade of research, putative normal physiological roles of LRRK2, and the various pathways that have been identified in the search for the mechanism(s) of its induction of neurodegeneration.
Investigating the Role of Leucine Rich Repeat Kinase 2 (LRRK2) in Human Induced Pluripotent Stem Cell Derived Macrophages
Author: Heyne LeeCharacterisation of Leucine-rich Repeat Kinase-2 Regulation and Kinase Function
Author: L. M. DunnPublisher:
ISBN:
Category :
Languages : en
Pages :
Book Description
Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are one of the most common causes of genetic Parkinson's disease (PD), with mutations thought to account for around 5% of all familial cases. LRRK2 is a large protein with a kinase and GTPase domain and multiple protein--protein interaction domains. Regulation of this protein is complex, with GTPase activity known to regulate kinase activity. Similarly, LRRK2 can autophosphorylate and is thought to form a dimer when active. Mutations in LRRK2 are numerous, with the most prevalent mutations occurring in the enzymatic core of this protein. This thesis describes work done to characterise the regulation and functioning of LRRK2, in order to further contribute towards understanding how mutations in this protein can lead to the pathogenesis of PD. Using BlueNative PAGE and glycerol gradient centrifugation, the quaternary structure of LRRK2 was assessed. In vitro kinase assays were used to characterise kinase activity of recombinant LRRK2 and a number of putative kinase substrates were also investigated. Identification of new kinase substrates was attempted and immunoprecipitation of LRRK2 to identify novel binding partners was also performed. Results of these experiments showed that familial mutations do not affect the ability of LRRK2 to form complexes. Instead, some mutations are affecting the enzymatic activity of LRRK2. Dephosphorylating LRRK2 showed that dimer formation is dependent on phosphorylation. Dephosphorylated forms of LRRK2 were more likely to be monomeric and displayed lower kinase activity than higher molecular weight forms. In vitro kinase assays to evaluate LRRK2 kinase substrates showed that [alpha]-synuclein is phosphorylated at low levels by G2019S but not wild-type LRRK2. Attempts to identify novel kinase substrates and binding partners of LRRK2 were unsuccessful, however evaluation of putative kinase substrates in vitro showed that DVL3 and TUBB5 may be good candidates for further investigation, as they were robustly phosphorylated by LRRK2. These results contribute towards our understanding of how LRRK2 functions and future studies based on these results may prove useful in aiding our understanding of how LRRK2 can cause PD pathogenesis.
Leucine-rich Repeat Kinase 2 (Lrrk2)
Author: Andrea MeixnerA Synopsis of Parkinson's Disease
Author: Md, Frcpc, Frcp (hon), Abdul Qayyum RanaPublisher: BoD – Books on Demand
ISBN: 9535112295
Category : Medical
Languages : en
Pages : 233
Book Description
Parkinsons disease is a disabling neurological condition with both motor and non-motor symptoms for which no cure is available at this stage. This book is unique in covering the most important topics related to Parkinsons disease. Current research and updates about some non-motor symptoms, as well as surgical treatment of Parkinsons disease, in addition to the long term complications of pharmacological treatments have been presented. This book can be used by physicians, researchers and neuroscientists who want to learn new information about these topics related to Parkinsons disease. Authors of the individual chapters are well known in their fields and the book has been edited by a world renowned Parkinsons disease expert.
Leucine-rich Repeat Kinase 2 (Lrrk2)
Author: Andrea MeixnerFunctional Characterization of Leucine-rich Repeat Kinase 2 (LRRK2) Dimerization
Author: Christian KleinGenetics, Neurology, Behavior, and Diet in Parkinson's Disease
Author: Colin R MartinPublisher: Academic Press
ISBN: 0128159510
Category : Medical
Languages : en
Pages : 764
Book Description
Genetics, Neurology, Behavior, and Diet in Parkinson's Disease: The Neuroscience of Parkinson’s Disease, Volume 2 provides a single source of material covering different scientific domains of neuropathology underlying this condition. The book covers a wide range of subjects and unravels the complex relationships between genetics, molecular biology, pharmaceutical chemistry, neurobiology, imaging, assessments, and treatment regimens. It fills a much-needed gap as a "one-stop" synopsis of everything to do with the neurology and neuroscience related to Parkinson’s disease—from chemicals and cells to individuals. It is an invaluable resource for neuroscientists, neurologists, and anyone in the field. Offers the most comprehensive coverage of a broad range of topics related to Parkinson's disease Serves as a foundational collection for neuroscientists and neurologists on the biology of disease and brain dysfunction Contains in each chapter an abstract, key facts, mini dictionary of terms, and summary points to aid in understanding Features preclinical and clinical studies to help researchers map out key areas for research and further clinical recommendations Serves as a "one-stop" source for everything you need to know about Parkinson’s disease
Crosstalk Between Leucine-rich Repeat Kinase 2 and MAPK Pathways
Author: Cindy Hsing-Liang HsuPublisher:
ISBN:
Category :
Languages : en
Pages : 340
Book Description
Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are prevalent causes of late-onset Parkinson's disease (PD). The LRRK2 kinase domain is homologous to that of the mixed-lineage kinases (MLKs), which are key members in the mitogen-activated protein kinase (MAPK) pathways important during cellular stress. We used co-immunoprecipitation and luciferase reporter assays to investigate the regulation of MAPK signaling by LRRK2 in human embryonic kidney cells. Our data demonstrate functional and physical links between LRRK2 and MAPK kinases MKK6, 3, and 7. We observed that LRRK2 binds to these MKKs through its carboxy-terminal of Ras (COR) and kinase domains and increases the activations of pro-apoptotic JNK and p38 cascades. Pathogenic LRRK2 mutations G2019S and R1441C specifically enhance the binding of LRRK2 to MKK6. Over-expression of LRRK2 and MKK6 result in the translocation of both kinases to the plasma membrane and endoplasmic reticulum. We also demonstrated that MKK6 may regulate LRRK2 function through phosphorylation. Dominant negative MKK6 reduces LRRK2 autophosphorylation, while MKK6 increases phosphorylation of kinase inactive LRRK2. RNAi knockdown of endogenous C. elegans MKK6 and p38 orthologs abolishes LRRK2-mediated protection against mitochondrial stress, demonstrating the importance of MKK6 for LRRK2 function. We also found that LRRK2 can interact with and increase the levels of JNK-Interacting Proteins (JIPs), scaffold proteins that bind MKKs and regulate the p38 and JNK cascades. Furthermore, evidence suggests that G2019S and R1441C mutations alter JIP function through the enhancement of its homodimerization. Our data demonstrate that there is a bidirectional modulation between MKK6 and LRRK2 through phosphorylation and subcellular localization. In addition, the JIPs might also function as modulators of LRRK2 subcellular translocation and activation. Our data propose an intriguing mechanism by which mutations in LRRK2 might lead to the activations of p38 and JNK cascades and apoptotic death associated with PD.