Paleologou K

Paleologou K.E., Oueslati A., Shakked G., Rospigliosi C.C., Kim H.Y., Lamberto G.R., Fernandez C.O., Schmid A., Chegini F., Gai W.P., et al. mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39 -syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces -syn protein degradation the autophagy and proteasome pathways, whereas the overexpression of -syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating -syn clearance and contribute MPL to the pathogenesis of PD. INTRODUCTION The tyrosine kinase c-Abl is involved in regulating several cellular processes and has been implicated in the development of the central nervous system (1) by controling neurogenesis, neurite outgrowth and neuronal plasticity (2C7). More recently, increasing evidence from various experimental model systems has also revealed that c-Abl is activated in neurodegenerative diseases (8) such as Alzheimer’s disease (AD) (9C11), Parkinson’s disease (PD) (12,13), NiemannCPick type C disease (14) and tauopathies (15). However, the mechanisms by which c-Abl contributes to the initiation and/or propagation of the pathogenic events underlying these neurodegenerative diseases remain poorly understood. c-Abl is a Fenipentol 120 kDa protein belonging to the cytoplasmic tyrosine kinase family. Similar to Src kinases, c-Abl possesses sequential SH3 and SH2 domains followed by a core catalytic domain with tyrosine kinase activity (16,17). Moreover, c-Abl has been detected in the nucleus and has a unique myristoylated N-terminal region that negatively regulates its kinase activity (16). The C-terminal region of c-Abl contains nuclear Fenipentol localization sequences and an F-actin-binding domain (16). c-Abl is a tightly regulated kinase and is activated through oxidative (18,19) or genotoxic stress (20), and the function of this protein is dependent on its subcellular localization (21C23). Cytoplasmic c-Abl regulates cellular adhesion and survival pathways, whereas c-Abl in the nucleus or in the mitochondria induces cell cycle arrest and apoptosis upon genotoxic stress (21,22,24). Changes in c-Abl levels or activation have been linked to the pathogenesis of AD. For example, the level of activated c-Abl (c-Abl phosphorylated at Y412, which is a marker of high kinase activity) is higher than normal in the hippocampus of AD patients (25) and c-Abl colocalizes with AD pathology in both AD human brains and transgenic (tg) animal models (8,11). In addition, c-Abl activation has been directly associated with the molecular mechanisms that govern amyloid beta-induced toxicity in primary hippocampal cultures (25). Together, these studies indicate that c-Abl acts at different stages in the amyloid cascade and affects both amyloid toxicity and Advertisement pathology, like the development of granulovacuolar degeneration systems and hyperphosphorylated tau (8,11,15). Many lines of proof have recommended that Fenipentol aberrant activation of c-Abl has important assignments in the pathogenesis of PD (12,13,26): (i) the c-Abl proteins level is normally upregulated in postmortem striatum of PD sufferers (26) as well as the phosphorylation of c-Abl at Y412 can be improved in the substantia nigra (12,26) and striatum (12) of PD sufferers; (ii) two unbiased studies show that c-Abl phosphorylates parkin and impairs its E3 ligase activity, resulting in lack of dopaminergic neurons in the substantia nigra (12,13); (iii) the inhibition of c-Abl activity by imatinib/Gleevec (27), nilotinib/Tasigna (28) or bafetinib/INNO-406 (29) protects against the increased loss of dopaminergic neurons in the substantia nigra of WT mice (12,26). Recently, Hebron demonstrated that c-Abl regulates the clearance of -syn (26), a synaptic proteins that is implicated in the pathogenesis of PD by proof from hereditary highly, pathological and pet modeling research (30). -Syn is normally a 14 kDa proteins that is within the intraneuronal insoluble fibrillar aggregates known as Lewy systems (Pounds) and Lewy neurites inside the brains of sufferers identified as having PD (31,32) and various other neurodegenerative -synucleinopathies, including dementia with Lewy systems (DLB) (33). The pathogenic relevance of -syn aggregation as well as the mechanism where these Pounds are formed stay subjects of extreme investigation and issue. However, the id of missense mutations in the gene in a few familial types of PD and proof that increased appearance because of gene duplication or triplication is enough to trigger familial types of PD possess strengthened the central function of this proteins in the etiology of both sporadic and familial situations of PD (34C42). Lately, Hebron provided proof for the bidirectional romantic relationship between -syn.