Search results for "LRRK2"
showing 7 items of 7 documents
Autophagy in the pathogenesis of ankylosing spondylitis
2016
The pathogenesis of ankylosing spondylitis (AS) is not well understood, and treatment options have met with limited success. Autophagy is a highly conserved mechanism of controlled digestion of damaged organelles within a cell. It helps in the maintenance of cellular homeostasis. The process of autophagy requires the formation of an isolation membrane. They form double-membraned vesicles called “autophagosomes” that engulf a portion of the cytoplasm. Beyond the role in maintenance of cellular homeostasis, autophagy has been demonstrated as one of the most remarkable tools employed by the host cellular defense against bacteria invasion. Autophagy also affects the immune system and thus is im…
Human R1441C LRRK2 regulates the synaptic vesicle proteome and phosphoproteome in a Drosophila model of Parkinson's disease
2016
International audience; Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset, autosomal dominant familial Parkinsons disease (PD) and variation at the LRRK2 locus contributes to the risk for idiopathic PD. LRRK2 can function as a protein kinase and mutations lead to increased kinase activity. To elucidate the pathophysiological mechanism of the R1441C mutation in the GTPase domain of LRRK2, we expressed human wild-type or R1441C LRRK2 in dopaminergic neurons of Drosophila and observe reduced locomotor activity, impaired survival and an age-dependent degeneration of dopaminergic neurons thereby creating a new PD-like model. To explore the function of LRRK2 variants in vivo, we …
Myocardial 123metaiodobenzylguanidine uptake in genetic Parkinson's disease.
2008
Myocardial (123)Metaiodobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac innervation. MIBG uptake is decreased in nearly all patients with Parkinson's disease (PD). Our objective was to evaluate MIBG uptake in patients with genetic PD. We investigated MIBG uptake in 14 patients with PD associated with mutations in different genes (Parkin, DJ-1, PINK], and leucine-rich repeat kinase 2 -LRRK2), in 15 patients with idiopathic PD, and 10 control subjects. The myocardial MIGB uptake was preserved in 3 of the 4 Parkin-associated Parkinsonisms, in I of the 2 patients with DJ-1 mutations, in 1 of the 2 brothers with PINK] mutations, in 3 of the 6 unrelated patient…
Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in lymphoma
2022
Inhibitors of the Bromo- and Extra-Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. Limited single-agent activity has been reported in the clinical setting. Here, we have performed a pharmacological screening to identify compounds that can increase the antitumor activity of BET inhibitors in lymphomas. The germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell lines OCI-LY-19 and WSU-DLCL2 were exposed to 348 compounds given as single agents at two different concentrations and in combination with the BET inhibitor birabresib. The combination partners included small molecules targeting important bi…
The Parkinson Disease Gene LRRK2: Evolutionary and Structural Insights
2006
Mutations in the human leucine-rich repeat kinase 2 (LRRK2) gene are associated with both familial and sporadic Parkinson disease (PD). LRRK2 belongs to a gene family known as Roco. Roco genes encode for large proteins with several protein domains. Particularly, all Roco proteins have a characteristic GTPase domain, named Roc, plus a domain of unknown function called COR. In addition, LRRK2 and several other Roco proteins also contain a protein kinase domain. In this study, I use a combination of phylogenetic and structural analyses of the COR, Roc, and kinase domains present in Roco proteins to describe the origin and evolutionary history of LRRK2. Phylogenetic analyses using these domains…
G2019S Variation in LRRK2: An Ideal Model for the Study of Parkinson's Disease?
2019
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and has plagued humans for more than 200 years. The etiology and detailed pathogenesis of PD is unclear, but is currently believed to be the result of the interaction between genetic and environmental factors. Studies have found that PD patients with the LRRK2:G2019S variation have the typical clinical manifestations of PD, which may be familial or sporadic, and have age-dependent pathogenic characteristics. Therefore, the LRRK2:G2019S variation may be an ideal model to study the interaction of multiple factors such as genetic, environmental and natural aging factors in PD in the future. This article reviewed the …
Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson’s Disease
2021
Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroau…