Neurodegeneration
is the progressive loss of structure or function of neurons, including death of
neurons1 .Cellular signaling is important for biological process
including growth,differentiation,apoptosis.Signal tansduction pathways play
major role in coordinating complex function of human body.Tyrosine
phosphorylation  is  one of the main mechanism in this pathway
that is carried  out by the enymes  protein tyrosine kinases (PTKs), which
catalyze the transfer of the ? phosphate of ATP to tyrosine residues on protein
substrates. Two classes of PTKs are present in cells: the Transmembrane receptor PTKs contain extracellular ligand binding
domain,transmembrane domain and intracellular catalytic domain. 2    They  transduce the extracellular signal to the
cytoplasm by phosphorylating tyrosine residues on the receptors themselves
(autophosphorylation) leads to activation of signal transduction cascade 3
Nonreceptor PTKs receptor tyrosine kinase relay intracellular signals;
they reside in the cytoplasm or in the nucleus rather than as transmembrane
proteins and are typically activated

by
interaction with a protein that is not an extracellular ligand.The RTK family includes the receptors for
insulin ,many growth factors, such as epidermal growth factor ,fibroblast
growth factorplatelet-derived growth factor, vascular endothelial growth factor

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and
nerve growth factor .Nonreceptor
tyrosine kinases includes Src and Abl. These kinases are triggered by RTKs
and G protein-coupled receptors and receptors of the immune system4.Dysregulation
of kinases leads to neurodegenrative diseases,cancer,inflammatorty diseases5

 

Parkinson
Disease

Parkinson’s
disease (PD) is a progressive neurodegenerative disorder due to a selective
loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc),
which leads to a decrease in the synthesis of dopamine (DA)6

Role Of Tyrosine
Kinase Receptor In Parkinson Disease

c-Abl Abelson
non-receptor tyrosine kinase, is activated by oxidative stress and thus
activation of c-Abl may play a role in neurodegenerative disorders7 .c-Abl
phosphorylation is increased in PD brain.MPTP 
metabolized by astrocytes in MPP + (1 –methyl1-4 phenyl pyridinium) .This
has toxicity for dopamenergic neuron and affects the survival  and functon of subtancia nigra .8Activated
c-Abl can phosphorylate parkin and MPP+ inhibit parkin’s E3 ligase function and
accumulate its toxic substrates, such as PARIS (PARkin Interacting Substrate),aminoacyl
tRNA synthetase complex-interacting multifunctional protein 2 and far upstream
element-binding protein 1.When parkin become  inactivated, PARIS levels increase,which cause
mitochondrial dysfunction results in the loss of dopamine neurons 9 .AIMP2
is contributor of the loss of DA neurons due to parkin inactivation10

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

STI-571
(Imatinib), a c-Abl inhibitor,
restores parkin’s E3 ligase activity, reduces the accumulation of parkin
substrates, and thereby protects against 1-methyl-4-phenylpyridinium
(MPP+)-induced neurotoxicity. The neuroprotection was an absence of tyrosine
phosphorylation of parkin and  upregulation of the parkin substrates, AIMP2
and FBP-1, was suppressed, suggesting that c-Abl inhibition was, in part,
protective through maintaining parkin in a catalytically active state .Inhibition
of c-Abl activation could be an effective disease modifying therapy for PD.11

 

 

 

 

 

 

 

 

During
sporadic PD, activated c-Abl tyrosine phosphorylates parkin, resulting in loss
of ubiquitin-ligase activity and leading to accumulation of toxic parkin
substrates and neuronal death. Imatinib
prevents parkin tyrosine phosphorylation by binding to c-Abl, restoring
parkin’s E3 ligase activity and cytoprotective function, thus protecting from
cell death and PD. C-Abl
tyrosine kinase inhibitor Nilotinib
(Tasigna®) is a second-generation inhibitor . It is potent with moderate brain
penetration and is more selective 12 . Substantial protection against DA
neuronal loss following MPTP intoxication is resulted by administration of
nilotinib13 .Src family kinases are also implicated in the signaling
of cytoskeletal changes, specifically those related to phagocytosis14
.Src kinase is often an activator of PI3K activity .Src kinase  role in the signal transduction pathway
linking LPS activation of TLR4 and NADPH oxidase activation  15.NADPH oxidase (Nox) family
enzymes are one of the main sources of cellular reactive oxygen species.The
activation of NADPH oxidase through the phosphorylation the p47phox subunit
,its activaton leads to production of superoxide  in microglia cells.Squamosamide derivative
FLZ  have neuroprotective effects in
parkinson disease .FLZ protected motor behavior via the elevation of dopamine
level. It protects apoptosis of dopamenergic neurons  in MPTP induce parkinson.16

 

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