Neurorestorative Effects Of FEZ1within Astrocytes On Pakinson’s Disease

Parkinson disease (PD) is a disorder characterized by a progressive loss ofdopaminergic neurons in the substantia nigra and depletion of the neurotransmitterdopamine in the striatum. The fasciculation and elongation protein zeta-1(FEZ1) is themammalian orthologue of the Caenorhabditis elegans UNC-76protein. Recent studieshave suggested that FEZ1participates in mammalian embryonic development of thecentral nervous system, and regulating dopaminergic neuron differentiation and dopaminerelease. In particular, abundant expression of FEZ1is seen in neurons of the adult rat brain.However, our recent work has shown that FEZ1gene were differentially expressed in twotypes of neonatal astrocytes cultured in vitro by microarray analysis, and further studydemonstrated that expression of this protein in astrocytes was not less than that in neurons.Furthermore, FEZ1may play important roles in human astrocytes, and mood stabilizersmight exert their cytoprotective and mood-stabilizing effects by inducing FEZ1expressionin astrocytes. In this study, We have evaluated FEZ1expression in the striatum andsubstantia nigra of a rat model of PD. We injected type-2astrocytes into PD rat，theninvestigated its influence on the improvement of the symptoms of PD rats and functionalreconstruction.Objective: To date, few studies on the expression patterns of FEZ1in PD have beenreported. The aim of this research is to investigate the expression and cellular location ofFEZ1in a rat model of PD, and explore the role of FEZ1in the pathogenesis and nerverepair of PD. We transplanted type-2astrocytes into the striatum of PD rat, then observedcellular dynamic changes and its neuroprotective effects.Methods: Male Sprague-Dawley rats were randomly divided into two groups: PDgroup and sham group. The models of PD were established by injecting6-OHDA in theright medial forebrain bundle of rats. Sham-lesioned rats were infused with equivalentsaline and served as controls. The expression of FEZ1mRNA and protein in the striatum and substantia nigra were examined by real-time PCR and Western blot.Immunohistochemistry was performed to identify the location of FEZ1in thesham-lesioned and PD rats. CM-DiI labeled type-2astrocytes were transplanted into thePD rat striatum by stereotactic injection, we detected the migration of the implanted cellsand evaluated nerve repair and PD symptoms improvement.Results: The typical ipsillateral rotations over210in30minutes were occurred in thesecond week.90%neurons of the right substantia nigra compacta(SNc) in lesioned side ofthe rat model of PD were not seen in Nissl dyeing and TH immunofluorescence staining.Western blot and real-time PCR analysis demonstrated that FEZ1was present in normal ratbrain striatum and substantia nigra. After lesioned, the expression of FEZ1graduallyincreased to a peak and then decreased. The expression of GFAP has the same tendency.Immunohistochemical detection showed a shift of FEZ1expression from tyrosinehydroxylase positive neurons in sham-lesioned rats to astrocytes in PD rat. Transplantationof type-2astrocytes improved rotation behavior in rats, implanted cells migrate tosubstantia nigra and other regions of the injection point in the striatum. In the substantianigra, TH and FEZ1expression was upregulated.Conclusions: Our results indicate that FEZ1appear to play a key role in regulatingdopaminergic neuron differentiation and dopamine release, and protecting dopamineneurons during the progression of PD. These findings provide a theoretical basis for apotential target of FEZ1in the treatment of PD.