Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease‐modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann‐Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

[1]  M. Vanier.  Niemann-Pick disease type C , 2010, Orphanet journal of rare diseases.

[2]  W. Bradley,et al.  The ALS/PDC syndrome of Guam and the cycad hypothesis. , 2009, Neurology.

[3]  Jürgen Götz,et al.  Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia , 2008, Proceedings of the National Academy of Sciences.

[4]  R. Ros,et al.  Parkin polymorphisms in progressive supranuclear palsy , 2008, Journal of the Neurological Sciences.

[5]  H. Bujard,et al.  The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy , 2008, The Journal of Neuroscience.

[6]  N. Hukriede,et al.  Generation of a transgenic zebrafish model of Tauopathy using a novel promoter element derived from the zebrafish eno2 gene , 2007, Nucleic Acids Research.

[7]  A. Hofman,et al.  Nonsteroidal Anti-Inflammatory Drugs and the Risk of Parkinson Disease , 2007, Neuroepidemiology.

[8]  M. Vitek,et al.  The Tau N279K Exon 10 Splicing Mutation Recapitulates Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Tauopathy in a Mouse Model , 2007, The Journal of Neuroscience.

[9]  Ayodeji A. Asuni,et al.  Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements , 2007, The Journal of Neuroscience.

[10]  E. Hirsch,et al.  Annonacin, a Natural Mitochondrial Complex I Inhibitor, Causes Tau Pathology in Cultured Neurons , 2007, The Journal of Neuroscience.

[11]  E. Mandelkow,et al.  Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model , 2007, Proceedings of the National Academy of Sciences.

[12]  L. Golbe,et al.  A clinical rating scale for progressive supranuclear palsy. , 2007, Brain : a journal of neurology.

[13]  Richard J Caselli,et al.  Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms. , 2007, American journal of human genetics.

[14]  B. Dubois,et al.  Atypical parkinsonism in Guadeloupe: a common risk factor for two closely related phenotypes? , 2007, Brain : a journal of neurology.

[15]  J. Wiltfang,et al.  Tauopathies and synucleinopathies: Do cerebrospinal fluid β-amyloid peptides reflect disease-specific pathogenesis? , 2007, Journal of Neural Transmission.

[16]  Bin Zhang,et al.  Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model , 2007, Neuron.

[17]  V. Meininger,et al.  Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: Report on the 142nd ENMC international workshop , 2007, Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.

[18]  M. Spillantini,et al.  Hereditary Frontotemporal Dementia Caused by Tau Gene Mutations , 2007, Brain pathology.

[19]  J. Lucas,et al.  Chronic lithium administration to FTDP‐17 tau and GSK‐3β overexpressing mice prevents tau hyperphosphorylation and neurofibrillary tangle formation, but pre‐formed neurofibrillary tangles do not revert , 2006, Journal of neurochemistry.

[20]  J. Kassubek,et al.  Neurofilament heavy‐chain NfHSMI35 in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes , 2006, Movement disorders : official journal of the Movement Disorder Society.

[21]  Tetsuaki Arai,et al.  LRRK2 Expression in Normal and Pathologic Human Brain and in Human Cell Lines , 2006, Journal of neuropathology and experimental neurology.

[22]  D. Karussis,et al.  Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. , 2006, Archives of neurology.

[23]  John Steele,et al.  Geographic isolates of atypical Parkinsonism and tauopathy in the tropics: Possible synergy of neurotoxins , 2006, Movement disorders : official journal of the Movement Disorder Society.

[24]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[25]  L. Buée,et al.  P1–062: Alzheimer's disease–like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits , 2006, The American journal of pathology.

[26]  N. Plesnila,et al.  An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Lucas,et al.  Full Reversal of Alzheimer's Disease-Like Phenotype in a Mouse Model with Conditional Overexpression of Glycogen Synthase Kinase-3 , 2006, The Journal of Neuroscience.

[28]  I. Litvan,et al.  Current and future treatments in progressive supranuclear palsy , 2006, Current treatment options in neurology.

[29]  Nick C Fox,et al.  Longitudinal MRI in progressive supranuclear palsy and multiple system atrophy: rates and regions of atrophy. , 2006, Brain : a journal of neurology.

[30]  D. D. C. P. Mrcp,et al.  MRI derived brain atrophy in PSP and MSA-P , 2006, Journal of Neurology.

[31]  Jean Féger,et al.  The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy , 2005, Journal of neurochemistry.

[32]  Bin Zhang,et al.  Axonal Degeneration Induced by Targeted Expression of Mutant Human Tau in Oligodendrocytes of Transgenic Mice That Model Glial Tauopathies , 2005, The Journal of Neuroscience.

[33]  K. Duff,et al.  Untangling memory deficits , 2005, Nature Medicine.

[34]  B. Hyman,et al.  Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function , 2005, Science.

[35]  Anna Barnes,et al.  FDG PET in the differential diagnosis of parkinsonian disorders , 2005, NeuroImage.

[36]  A. Lees,et al.  Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. , 2005, Brain : a journal of neurology.

[37]  W. Noble,et al.  Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Trojanowski,et al.  Transgenic Mouse Model of Tau Pathology in Astrocytes Leading to Nervous System Degeneration , 2005, The Journal of Neuroscience.

[39]  E. Mandelkow,et al.  Anthraquinones Inhibit Tau Aggregation and Dissolve Alzheimer's Paired Helical Filaments in Vitro and in Cells* , 2005, Journal of Biological Chemistry.

[40]  Chi Li,et al.  Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D W Dickson,et al.  Autosomal dominant parkinsonism associated with variable synuclein and tau pathology , 2004, Neurology.

[42]  Jean Féger,et al.  Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe , 2003, Journal of neurochemistry.

[43]  P Champy,et al.  The mitochondrial complex i inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism , 2003, Neuroscience.

[44]  Tony Hunter,et al.  Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration , 2003, Nature.

[45]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[46]  R. Berry,et al.  Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Bin Zhang,et al.  Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Irene Litvan,et al.  Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia , 2003, Annals of neurology.

[49]  J. Lucas,et al.  Spatial learning deficit in transgenic mice that conditionally over‐express GSK‐3β in the brain but do not form tau filaments , 2002, Journal of neurochemistry.

[50]  Hirotaka Yoshida,et al.  Abundant Tau Filaments and Nonapoptotic Neurodegeneration in Transgenic Mice Expressing Human P301S Tau Protein , 2002, The Journal of Neuroscience.

[51]  T. Hashikawa,et al.  Tau filament formation and associative memory deficit in aged mice expressing mutant (R406W) human tau , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[52]  I. Ferrer,et al.  Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration , 2002, Acta Neuropathologica.

[53]  D. Geschwind,et al.  Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila , 2002, Neuron.

[54]  Charles Duyckaerts,et al.  Guadeloupean parkinsonism: a cluster of progressive supranuclear palsy-like tauopathy. , 2002, Brain : a journal of neurology.

[55]  Merle Ruberg,et al.  Toxicity of Annonaceae for dopaminergic neurons: Potential role in atypical parkinsonism in Guadeloupe , 2002, Movement disorders : official journal of the Movement Disorder Society.

[56]  Akihiko Takashima,et al.  Formation of Filamentous Tau Aggregations in Transgenic Mice Expressing V337M Human Tau , 2001, Neurobiology of Disease.

[57]  A J Lees,et al.  Familial progressive supranuclear palsy: detection of subclinical cases using 18F-dopa and 18fluorodeoxyglucose positron emission tomography. , 2001, Archives of neurology.

[58]  Joshua M. Shulman,et al.  Tauopathy in Drosophila: Neurodegeneration Without Neurofibrillary Tangles , 2001, Science.

[59]  Russell H. Swerdlow,et al.  Further Evidence for Mitochondrial Dysfunction in Progressive Supranuclear Palsy , 2001, Experimental Neurology.

[60]  René Hen,et al.  Decreased nuclear β‐catenin, tau hyperphosphorylation and neurodegeneration in GSK‐3β conditional transgenic mice , 2001 .

[61]  R. Nitsch,et al.  Tau Filament Formation in Transgenic Mice Expressing P301L Tau* , 2001, The Journal of Biological Chemistry.

[62]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[63]  Wen-Lang Lin,et al.  Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein , 2000, Nature Genetics.

[64]  R. A. Crowther,et al.  Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein , 2000, Acta Neuropathologica.

[65]  P. Davies,et al.  Characterization of Pathology in Transgenic Mice Over-Expressing Human Genomic and cDNA Tau Transgenes , 2000, Neurobiology of Disease.

[66]  H. Geerts,et al.  Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. , 1999, The American journal of pathology.

[67]  Bin Zhang,et al.  Age-Dependent Emergence and Progression of a Tauopathy in Transgenic Mice Overexpressing the Shortest Human Tau Isoform , 1999, Neuron.

[68]  I Litvan,et al.  Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias , 1999, Neurology.

[69]  H. Braak,et al.  Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes , 1999 .

[70]  Alexis Elbaz,et al.  Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study , 1999, The Lancet.

[71]  I Litvan,et al.  Association of an extended haplotype in the tau gene with progressive supranuclear palsy. , 1999, Human molecular genetics.

[72]  N. Murakami.  [Parkinsonism-dementia complex on Guam]. , 1999, Ryoikibetsu shokogun shirizu.

[73]  A Klug,et al.  Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[74]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[75]  M. Hallett,et al.  Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) , 1996, Neurology.

[76]  I Litvan,et al.  Validity and Reliability of the Preliminary NINDS Neuropathologic Criteria for Progressive Supranuclear Palsy and Related Disorders , 1996, Journal of neuropathology and experimental neurology.

[77]  H. Ninomiya,et al.  [Niemann-Pick disease type C]. , 2001, Nihon rinsho. Japanese journal of clinical medicine.

[78]  A J Lees,et al.  Familial progressive supranuclear palsy. Description of a pedigree and review of the literature. , 1995, Brain : a journal of neurology.

[79]  P. Mcgeer,et al.  The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases , 1995, Brain Research Reviews.

[80]  M. Goedert,et al.  Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. , 1995, The EMBO journal.

[81]  G. Drewes,et al.  Glycogen synthase kinase‐3 and the Alzheimer‐like state of microtubule‐associated protein tau , 1992, FEBS letters.

[82]  P. Mcgeer,et al.  Anti-inflammatory drugs and Alzheimer disease , 1990, The Lancet.