Download - ACNR

CONFERENCE REPORTSModels in Parkinson’s Research:Are we addressing the right questions?Conference details: 18 May 2011; London, UK. Reviewed by: Dr Rosemary Fricker, Senior Lecturer, Keele University, UK.The Seventh Research Conference of theUK Special Parkinson’s Research InterestGroup (SPRING) brought togetherleading scientists and clinicians from acrossthe globe to debate the value of currentmodels of Parkinson’s disease (PD). The aimof this one day meeting was to discuss theusefulness of current PD models in broadeningour understanding of the diseaseprocess, and as a tool to test future therapies.The first session set the scene by identifyingthe key features of PD that need to bereproduced in models. Jose Obeso (NavarraMedical School, Spain) and Tamas Revesz(UCL, London) described the complexity ofneurodegeneration in PD, which affectsmany neuron subtypes and not solely thenigrostriatal dopamine neurons, causing along phase of preclinical pathology, andevolving not only the cardinal motor symptomsbut also cognitive impairments anddementia seen in PD. In addition, neuronalpathology appears as Lewy neurites inneuronal processes as well as Lewy bodieswithin cells, suggesting that problems withneurotransmission may be a key componentof the disease process. There was somedisagreement as to whether PD pathology issynchronised and multisystemic, or if itspreads in a caudo-rostral fashion from oneregion to another (the Braak hypothesis).However, both speakers concluded that anideal animal model should incorporate: agedependentand focal loss of dopamineneurons with associated motor dysfunction,Lewy body and Lewy neurite pathology, andprogressive neurodegeneration that representsthe non-motor components of thedisease.The second session focussed more specificallyon rodent models of PD. TimGreenamyre (Pittsburgh University, USA) gavean eloquent overview of the rotenone modeldeveloped in his laboratory, highlighting thestrengths of this toxin-induced neuron degeneration.Rotenone targets complex 1 in themitochondria, inhibiting mitochondrial respirationand thus energy metabolism.Greenamyre’s group have observed iron depositionin the substantia nigra pars compacta(SNc) following rotenone administration,suggesting that iron may contribute to thepathology of the disease.Peter Magill (Oxford University) reportedwork to elucidate the nature of neuronalfiring patterns in the basal ganglia circuitry,and how these are affected in PD to cause anincrease in bradykinesia and rigidity. Injecting6-hydroxydopamine into the basal ganglia(the 6-OHDA rat model) causes large changesRosemary Fricker is a Senior Lecturer at Keele UniversityMedical School. Her current research is focussed onidentifying novel proteins that influence the differentiationof stem cells to dopamine neurons, for the treatment ofParkinson's disease.in the β oscillation firing patterns of basalganglia neurons, with increased synchrony ofpairs of neurons, particularly within theGlobus Pallidus (GP). A single GP neuron caninnervate neurons in the GP, entopeduncularnucleus, subthalamic nucleus and substantianigra pars reticulata. Thus, death of SNcdopaminergic neurons may cause wholenetworks of neurons to undergo changes inrhythm, oscillation and synchrony and, byfiring at the wrong time or in the wrong placewithin the basal ganglia, cause many of thesymptoms of PD.Dysfunction of the proteasome in clearingunwanted proteins from neurons is a candidatepathway that may be involved in thedevelopment of idiopathic PD. Dr LynnBedford (Parkinson’s UK Senior Fellow,Nottingham University) presented her work todevelop a genetic mouse model, by conditionaldeletion of the 26S proteasome in tyrosinehydroxylase positive neurons. Mice withthis deletion show progressive neurodegenerationand the formation of Lewy-like inclusionscontaining α-synuclein, ubiquitinatedproteins and mitochondria. However, whenthese mice were crossed with α-synuclein nullmice, lack of α-synuclein had no effect onLewy body formation, suggesting that it maynot be a key player in the process.The third session of the conferencefocussed on modelling PD in other animalsand human cellular systems. Tilo Kunath(Parkinson’s UK Senior Fellow, EdinburghUniversity) presented research to generateinduced pluripotent stem cell lines (iPSCs)from a patient with familial PD caused by triplicationof the SNCA gene encoding α-synuclein.These iPSCs were differentiated intomidbrain dopamine neurons and were shownto express double the levels of α-synucleinwhen compared to neurons derived fromiPSCs generated from an unaffected familymember.Animals such as zebra fish, Caenorhabditiselegans and Drosophila have been used tomodel neurodegenerative disease and offeradvantages such as short life cycles, relativelystraightforward gene manipulation, simplicityor easier visualisation of neuronal circuitry,and the potential to screen large numbers ofanimals for pathology or potential therapies.Oliver Bandmann (Sheffield University)described techniques by his group for transientknock down of the PD-related genes DJ-1, parkin and PINK1 by injecting antisenseoligonucleotides into zebrafish embryos atthe single cell stage. This morpholino strategycan generate stable lines that display keyfeatures of PD such as mitochondrial dysfunctionand loss of dopaminergic neurons.Anton Gartner (Dundee University)presented research to generate PD models inC.elegans via α-synuclein gene mutation orusing the 6-OHDA toxin to induce neurodegeneration.Using the 6-OHDA model toscreen for neuroprotective genes, they havefound that the membrane protein tetraspanin-17 may have a neuroprotective role fordopamine neurons depending on its specificexpression level. Alex Whitworth (SheffieldUniversity), presented data on Drosophilamodels of PD derived by mutating the genes:PINK1 and Rhomboid-7. Their researchsuggests that aberrant fusion of mitochondriastops their degradation and this may play arole in neuronal death in PD.The conference ended with an opendiscussion between the audience and apanel of experts: Paul Bolam, Oxford; KieranBreen, Parkinson’s UK; Jose Obeso, Navarra;Richard Wade-Martins, Oxford; and RosemaryFricker, Keele. Many issues were raisedincluding: is PD a syndrome rather than asingle disease, and should we therefore bedeveloping more complex models, or indeedusing humans as models? Which modelsmight be most useful for the pharmaceuticalindustry, enabling better therapeutics to bedeveloped for early PD? One of the problemsdiscussed was the lack of biomarkers formodels, particularly for in vivo imaging ofrodents and primates to assess neuron degenerationand repair. The final conclusion? Weshould continue with both current and newavenues of research, as all models are goodbut none are yet sufficient. lACNR > VOLUME 11 NUMBER 4 > SEPTEMBER/OCTOBER 2011 > 35