Brain Structure And Function Of DJ-1 Konckout Parkinsonism Model Mouse:An MRS/MRI Study

Parkinson’s disease(PD)is the second most common neurodegenerative disease after Alzheimer’s disease(AD)and susceptible to aged person.The occurrence and development of PD is always accompanied by abnormal changes in brain structure and metabolite function.At present,there is no completely effective and curable method for the treatment of PD in clinic.It is the consensus for clinician to achieve early diagnosis,delay the disease process and relieve symptoms.The establishment of PD animal model could provides convenience and basis for preclinical research and the formulating effective treatment schemes of the disease.DJ1 is closely related to human PD,many reports at the cell level in vitro have found that the deletion of DJ-1 gene will cause oxidative metabolism disorder,insufficient energy supply and apoptosis of neurons.The research on the changes of brain structure and function in DJ-1 knockout mice have not been reported by now.With the rapid development of magnetic resonance imaging/spectroscopy(MRI/MRS),unbiased research on brain structure and metabolite function at the whole brain level in vivo has become a availiable and economical way.In addition,under complex physiological conditions in vivo,the indirect measurement method of in vivo magnetic resonance spectrum/image and the lack of stable and accurate internal reference could introduce unnecessary trouble to the interpretation of in vivo magnetic resonance analytical results.Especially in the aged brain with neurological/mental diseases,its interference factors are various and complex.Therefore,the work of this doctoral thesis combined in vivo MRI/MRS,matrix assisted laser desorption/ionization-mass spectrometry imaging(MALDI-MSI)and laser ablation-inductively coupled plasma mass spectrometry(LA-ICP-MS)to study the brain structure and metabolic changes of aged and adult DJ-1 knockout mice,and the effect of MK801 on the motor ability of DJ-1 knockout mice is also argued.The specific work is as follows:(1)The changes of metabolites in mPFC of aged DJ-1 knockout mice were studied by MRS and MALDI-MSI.It was found that the metabolism of GSH and GSH/Glu were significantly increased in DJ-1 knockout mice,and Glu was regional difference in mPFC and FrA.These results suggest that the abnormal metabolism of GSH and Glu means the DJ-1 knock-out mice have abnormal oxidative stress and excitatory cytotoxicity,and the increased GSH in the mPFC of DJ-1 mice which might represent a compensatory mechanism in response to elevated regional oxidative stress induced by loss of DJ-1 function.The results of this work highlighted the need to be cautious when interpreting the in vivo 1H-MRS results obtained from aged transgenic animals,in which the concentration of traditionally used internal reference could no longer be assumed to be the same as that in the age-matched wild type animals.(2)The abnormality of Fe deposition in the whole brain of DJ-1 knockout aged mice was studied.The results showed that there were abnormal MRI signals in the prefrontal association cortex,accumbens and parietal association cortex in DJ-1 knockout mice.The significantly increased Fe in the prefrontal association cortex was also detected by LA-ICP-MS,and it was found that the Fe deposition in this brain region was consistent with the increase of QSM signal,at the same time,MALDI-MSI results showed that there was an significantly decreased Cr and increased trends in Gln,Glu,GSH and Tau in the same region.These results suggest that the Fe was deposized in a multi-brain region way in DJ-1 knockout mice,which can be confirmed by in vivo QSM technology.The disorder of Fe metabolism is accompanied with the abnormality of energy metabolism and oxidative metabolism which together promote the deterioration of PD.(3)The changes of whole brain volume and metabolites in DJ-1 knockout adult mice and the effect of MK801 on the motor ability were studied.It was found that the DJ-1 knockout male and female mice had abnormal atrophy and metabolic disorder in striatum.The difference is that male mice have obvious volume atrophy in the motor cortex,while female mice have obvious volume atrophy in the cingulate cortex.In addition,the open field experiment showed that MK801 could significantly increase the movement distance of DJ-1 knockout mice and alleviate their anxiety behaviour,while WT mice did not behave the same reaction.These results suggest that there were structural and functional abnormalities in the striatum of both male and female DJ-1 knockout adult mice,and different gender behaved differently in cortical region.DJ-1 knockout mice are especially sensitive to MK801,which is related to its basally striatal abnormalities.In conclusion,we found abnormal GSH and Fe metabolism in aged DJ-1 knockout mice.These results are consistent with MALDI-MSI and LA-ICP-MS results.In addition,adult DJ-1 knockout mice have structural and functional abnormalities in multiple brain regions,which are the basis of their abnormal sensitivity to MK801.These findings provide a new sight for us to understand the pathological mechanism of DJ-1 gene and suggested that the metabolic abnormalities of Glu,GSH and Fe may play an important role in the course of PD.