title: No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra.
abstract: See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation can ameliorate parkinsonian motor features and is likely to counteract the manifestation of parkinsonism in SCA2 and SCA3 despite a severe neurodegeneration of the dopaminergic substantia nigra.
authors.affiliation: 1 Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany 2 Deutsches Zentrum für Neurodegenerative Erkrankungen, D-72076 Tübingen, Germany Ludger.Schoels@uni-tuebingen.de.
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.affiliation: 3 Department of Nuclear Medicine, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Reimold
authors.affiliation: 4 Dr Senckenbergisches Chronomedizinisches Institut, Goethe-University, D-60590 Frankfurt/Main, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Seidel
authors.affiliation: 1 Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Globas
authors.affiliation: 1 Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen, Germany 2 Deutsches Zentrum für Neurodegenerative Erkrankungen, D-72076 Tübingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Brockmann
authors.affiliation: 5 Department of Neuroradiology, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Till Karsten
authors.initials: TK
authors.lastname: Hauser
authors.affiliation: 6 Molecular Neurogenetics, Department of Neurology, Goethe-University, D-60590 Frankfurt/Main, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.affiliation: 7 Department of Neurology, Philipps University of Marburg, D-35039 Marburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Bürk
authors.affiliation: 8 Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, NL-9700 RB Groningen, The Netherlands.
authors.forename: Wilfred
authors.initials: W
authors.lastname: den Dunnen
authors.affiliation: 9 Radiopharmacy, University of Tübingen, D-72076 Tübingen, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Reischl
authors.affiliation: 4 Dr Senckenbergisches Chronomedizinisches Institut, Goethe-University, D-60590 Frankfurt/Main, Germany.
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
authors.affiliation: 10 Department of Neurology, University Medical Center Groningen, University of Groningen, NL-5970 RB Groningen, The Netherlands.
authors.forename: Ewout R
authors.initials: ER
authors.lastname: Brunt
authors.affiliation: 4 Dr Senckenbergisches Chronomedizinisches Institut, Goethe-University, D-60590 Frankfurt/Main, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000067698:Ataxin-2 / Q000235:genetics; D000067699:Ataxin-3 / Q000235:genetics; D016022:Case-Control Studies; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D017827:Machado-Joseph Disease / Q000150:complications / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D017072:Neostriatum / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000000981:diagnostic imaging; D020734:Parkinsonian Disorders / Q000150:complications / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D012097:Repressor Proteins / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D013378:Substantia Nigra / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion; D055815:Young Adult
chemical_list: C000593752:ATXN2 protein, human; D000067698:Ataxin-2; D050483:Dopamine Plasma Membrane Transport Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: PET; parkinsonism; spinocerebellar ataxias; substantia nigra; subthalamic nucleus