【医院科室学习-神经生物学】_基底神经节疾病.pptVIP

4.UCH-L1/PARK5utative kinase 1 (PINK1) Ubiquitin carboxyl-terminal hydrolase L1 neuron-specific protein PGP 9.5 one of the most abundant proteins in the brain (2%) hydrolytic activity, ligase activity and binding mono-ub Possible role of UCH-L1 in PD. Mechanisms of neurotoxicant-induced proteasome dysfunction and dopaminergic degeneration. Transgenic animal model alpha-synuclein A30P+A53T, LRRK2(R1441G), parkin, R621C synphilin-1 … mouse, C. elegans , Drosophila, zebrafish Inflammation Neuroinflammation is mediated predominately by microglia, the resident immuno-competent and phagocytic cells within the CNS. Microglia, representing 5?20% of brain cells Microglial cell density in the SN is 4?5 times higher than in other regions Activated cells also produce pro-inflammatory molecules Schematic representation of lipopolysaccharide(LPS)-induced and glial activation-mediated dopamine (DA) neurodegeneration. Key molecular mechanisms that are widely accepted to contribute to the neurodegenerative process in dopaminergic neurons in the substantia nigra in Parkinson disease. At least two of the three major symptoms are present. Possible causes for symptoms Response to levodopa The main tools used to make a diagnosis: Neurological examination Motor physiology tests Neuro-imaging: PET(18-flurodopa ),CT, MRI Lewy bodies during autopsy (gold standard) Diagnosis Treatment There is no known cure for Parkinsons disease. Treatment is aimed at controlling the symptoms. Medications control symptoms primarily by controlling the imbalance between the transmitters. Therapeutic strategy Directly improve the function of dopamine neurotransmission Indirectly improve the function of dopamine Surgery and deep brain stimulation dopamine↑ in the brain Precursor Rate-limiting step , decrease in PD L-dopa Peripheral inhibitors The central and peripheral metabolism of levodopa and its modification by drugs. Circuit of Basal Ganglia Direct pathway In