title: Loss of dopaminoreceptive neuron causes L-dopa resistant parkinsonism in tauopathy.
abstract: Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a family of inherited dementias caused by tauopathy. A mutation in exon 10 of the tau gene, N279K, causes a particular kindred of FTDP-17, which is predominant for parkinsonism. The disease initially presents as L-dopa resistant parkinsonism which then rapidly progresses. The final pathological features reveal disappearing dopamine (DA) neurons, but the causes remain poorly understood. We previously established a transgenic mouse with human N279K mutant tau as a model for FTDP-17, which showed cognitive dysfunctions caused by the mutant. Here we analyze L-dopa resistant parkinsonism by several behavioral tests, and focus on the distributions and accumulations of the mutant tau in the DA system by immunohistochemistry and Western blot. Interestingly, dopaminoreceptive (DAr) neurons in the striatum showed neurofibrils degeneration and apoptosis through caspase-3 activation by mutant tau accumulation. The DAr neuron loss in the caudoputamen, the target of the nigrostriatal system occurred before DA neuron loss in young symptomatic mice. Residual DA neurons in the mouse functioned in DA transportation, whereas dysregulation of intracellular DA compartmentalization implied an excess level of DA caused by DAr neuron loss. In the final stages, both DAr and DA neurons decreased equally, unlike Parkinson's disease. Therefore, DAr neurons were fundamentally vulnerable to the mutation indicating a critical role for the L-dopa resistant parkinsonism in tauopathy.
authors.affiliation: Department of Pathology and Cell Biology, University of the Ryukyus Graduate School of Medicine, Okinawa, Japan. chibas@med.u-ryukyu.ac.jp
authors.forename: Shunmei
authors.initials: S
authors.lastname: Chiba
authors.forename: Erika
authors.initials: E
authors.lastname: Takada
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tadokoro
authors.forename: Taizo
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kadoyama
authors.forename: Mariko
authors.initials: M
authors.lastname: Takenokuchi
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Noboru
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000032:analysis; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D059290:Dopaminergic Neurons / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009454:Neurofibrils / Q000473:pathology; D009483:Neuropsychological Tests; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology*; D011699:Putamen / Q000187:drug effects / Q000473:pathology; D024801:Tauopathies / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics*
chemical_list: D000978:Antiparkinson Agents; C054369:MAPT protein, human; D016875:tau Proteins; D007980:Levodopa; C505410:Casp3 protein, rat; D053148:Caspase 3