Jian Feng's PowerPoint Presentation - University at Buffalo

Finding a Cure for Parkinson’s DiseaseJian Feng, Ph.D.Professor of Physiology and BiophysicsState University of New York at Buffalo

Fly by WireBlue AngelsMichael JordanMajor Axon Tracks in Human Brain

Parkinson’s disease is caused by the death of dopamine neuronsmovementstriatumdopamine100 billion neurons100 trillion synapses20 Wattssubstantia nigra

pesticidesherbicidesheavy metalsEnvironmentGenes• parkin• α-synuclein• DJ-1• PINK1• LRRK2• othersLoss ofDA Neuronsin SNDysfunction ofBasal GangliaClinical SymptomsTremor, Rigidity, Akinesia, Postural instability, etc.

TH + Neurons in the Rat BrainTH Staining1 mmStriatumSN1x4x4.1 mm

Massive Axonal Branches of A Single Rat Nigral Dopamine NeuronFrom Matsuda et al. J Neurosci. (2009)Dimension Volume % Total VolumeCell Body: 20 µm x 10 µm ellipsoid 1600 µm 3 0.7%Primary Axon: 7.7 mm x 0.8 µm tube 3900 µm 3 1.7%Axon Bushes: 45 cm x 0.8 µm tube 226000 µm 3 97.6%99.3% of cell volume in a single axon

BuffaloNew YorkIf the dopamine neuronwere the size of Buffalo,the axon would go allthe way to New YorkCity, run through all thestreets in NYC.

Rat Dopamine Neurons in Culture1.8mmTH + MAP27 day Midbrain Culture

Parkinson’s DiseaseGenetic Factors:ParkinTaxol,Neurotrophins,mGluRIIIEnvironmental Factors:RotenoneMicrotubulesDA v DA svreleaseDA cROSSelective Deathof DA Neurons

Size MattersSpecies Brain Weight Length of DA axonMouse 0.4 g ~ 25 cmRat 2 g 45 cm *Rhesus Monkey 95 g ~ 160 cmHuman 1350 g ~ 400 cmEstimates based on cube root of weight* From Matsuda et al. (2009) J Neurosci.

Induced Pluripotent Stem CellsShinya YamanakaLasker Award 2009Oct4, Sox2,Klf4, MycICMFrom New York Times, 11/21/2007

From Skin Cells to Midbrain Dopamine NeuronsA small piece of skinNeuronsSkin cellsStem CellsTH/En-1DA Neurons

Parkin Controls Dopamine UtilizationparkinDopamine neuronMAODA Free radicalsparkinSpontaneousrelease(leakage)parkindopaminedopaminetransporterdopaminereceptorsstriatal neuronParkin enhances precision of dopamine signals while limiting dopamine toxicity

Treating Parkinson’s Disease: Present and FutureCurrent Therapies: symptom management• dopamine agonists: mimic the action of dopamine on its receptors• L-DOPA/carbidopa: increase dopamine concentration in the brain• MAO-B inhibitors: reduce the breakdown of dopamine• COMT inhibitors: reduce the breakdown of dopamineFuture Therapies: prevent or slow down the death of dopamine neurons• Biomarkers: predict PD and track its progression• Disease-modifying drugs: e.g. mimic the protective functions of parkin• Cell transplantation: iPS cells, iDA cells, etc.

AcknowledgementsFeng LabHoubo Jiang, Ph.D.Yong Ren, Ph.D.Zhixing Hu, Ph.D.Mahboobe Ghaedi, Ph.D.Jianbo Wu, Ph.D.Zhonghai Yan, Ph.D.State Univ of New York at BuffaloZhen Yan, Ph.D.Ping Zhong, Ph.D.Eunice Yuen, Ph.D.Roswell Park Cancer InstituteBarbara Foster, Ph.D.Gissou Azabdaftari, M.D.Jingxin Qiu, M.D., Ph.D.Tottori University, JapanKazuhiro Nakaso, M.D.Zhejiang University, ChinaBaorong Zhang, M.D.INSERM, FranceAlexis Brice, M.D.University of Wisconsin - MadisonSu-chun Zhang, Ph.D.Johns Hopkins UniversityLinzhao Cheng, Ph.D.Massachusettes Institute of TechnologyRudolf Jaenisch, Ph.D.Frank Soldner, Ph.D.Michael J. Fox Foundation, NYSTEM, NIH, SUNY REACHSpecial thanks to PD patients, their families and their physicians.