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Parkinson’s disease Aim Review quickly control of movement Symptoms of PD “Causes” of PD Environment Genetic Treatment Current Potential Human Brain Introduction Mechanisms of motor control of behavior Reflex Involuntary Voluntary Understanding from analysis of neural diseases Spinal reflex Descending control of motoneurons feedback and feedforward control ff = anticipation primary motor cortex somatotopic map neurons project to groups of muscles for coordinated act Primary motor cortex Primary motor cortex stimulation gives movement fire before voluntary movement Role of brainstem nuclei Major pathway in voluntary movements starts in association cortex caudate and putamen input globus from substantia nigra pallidus thalamus ends in motor cortex Circuit Schematic circuit from association (neocortex) to motor cortex Huntington’s disease symptoms: faster jerky movements gene for protein huntingtin (Htt) on chromosome 4 mutates to include CAG (glutamine) repeats gene repeats increase easily Htt may disrupt synaptic transmission Neural circuit caudate neurons [GABA] degenerate, less inhibition of thalamus increased excitation of cortex more movement Parkinson’s disease symptoms: hard to initiate and maintain movements (bradykinesia) PD associated with DA loss death of dopaminergic substantia nigra neurons dying cells have Lewy bodies, made up of neurofilaments Lewy bodies Immunoreactive to a-synuclein ubiquitin a-synuclein may be misfolded Adding ubiquitin to lys marks protein for degradation via proteasome Parkinson’s disease Loss of dopaminergic neurons normal: 4% per decade Parkinson’s: 70-80% loss normal substantia nigra Parkinson’s Changes to circuit more tonic inhibition of thalamus decreased excitation of cortex Therapy - today L-DOPA cross blood-brain barrier dopamine agonists MAO-B inhibitors (selegiline = deprenyl) cell replacement fetal midbrain transplants pigs carotid body stem cells deep brain [=subthalamic nuclei] stimulation Dyskinesia result of >5 years LDOPA administration normal L-DOPA may be taken up by 5-HT neurons use 5-HT agonists How does DBS work ? stimulation ?? inactivates STN neurons, producing a functional lesion activates the STN output may reduce burstiness http://jn.physiology.org/cgi/content/abstract/103/2/962 Parkinson’s summary death of dopaminergic substantia nigra neurons hard to initiate and maintain movements (bradykinesia) more tonic inhibition of thalamus decreased excitation of cortex dopaminergic therapy What causes PD: Approaches epidemiology genetic chromosome gene / protein pharmacology anatomical post-mortem MRI/PET animal models Parkinson’s disease mimic with MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine metabolise to MPP+ 1-methyl-4-phenylpyridinium Causes ? Animal model Model with MPTP MPP+ Neuronal damage, activates microglia, which produce NO (iNOS), causes further neuronal damage PD Causation - genetics Inherited disorder *a-synuclein (folds SNAREs) Parkin (E3 ubiquitin ligase) DJ-1 (stress response chaperone) PINK-1 (mitochondrial protein kinase) *LRRK2 (another ?mitochondrial kinase) It is not clear why mutations in a-synuclein, or parkin or [] genes cause nigral dopaminergic cell death in familial PD [Le W & Appel SH (2004)] *dominant – others are recessive Causation Environmental factors too Rotenone fish poison blocks mitochondrial function upregulates a-synuclein oxidises DJ-1 Paraquat A model of PD Fly models say: Heat shock proteins (HSP) a-synuclein stimulates chaperone production Geldanamycin GST (glutathione – S - transferase) parkin antioxidants Role for rapamycin parkin, pink1, LRRK2 Mitochondrial fission/fusion affected Mitochondrial fission/fusion Gene therapy for the future? GDNF Glial cell-line derived neurotrophic factor Open label trial ok, but … pump GAD (Glutamic Acid Decarboxylase) mimic GABA in subthalamic nuclei AADC-2 aromatic L-amino-acid decarboxylase enzyme that synthesises DA parkin lentivirus adenovirus Summary death of dopaminergic substantia nigra neurons hard to initiate and maintain movements (bradykinesia) more tonic inhibition of thalamus decreased excitation of cortex mimic with MPTP (metabolise to MPP+) dopaminergic therapy potential drug therapy potential gene therapy To Ponder Parkinson’s has well-defined deficit – loss of dopaminergic cells well-described pathology & behaviour variety of therapies no cure no known cause