Original Paper

Acta Neuropathologica

, Volume 120, Issue 4, pp 449-460

Open Access This content is freely available online to anyone, anywhere at any time.

Axonal inclusions in spinocerebellar ataxia type 3

  • Kay SeidelAffiliated withDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of GroningenInstitute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, J. W. Goethe University Email author 
  • , Wilfred F. A. den DunnenAffiliated withDepartment of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen
  • , Christian SchultzAffiliated withInstitute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, J. W. Goethe UniversitySection of Neuroanatomy, Center for Biomedicine and Medical Technology Mannheim (CBTM), Medical Faculty Mannheim, Ruprecht Karls-University Heidelberg
  • , Henry PaulsonAffiliated withDepartment of Neurology, University of Michigan
  • , Stefanie FrankAffiliated withInstitute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, J. W. Goethe University
  • , Rob A. de VosAffiliated withLaboratorium Pathologie Oost Nederland
  • , Ewout R. BruntAffiliated withDepartment of Neurology, University Medical Centre Groningen, University of Groningen
  • , Thomas DellerAffiliated withInstitute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, J. W. Goethe University
  • , Harm H. KampingaAffiliated withDepartment of Cell Biology, University of Groningen
    • , Udo RübAffiliated withInstitute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, J. W. Goethe University

Abstract

Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3 (SCA3 or Machado–Joseph disease), although these inclusions are not thought to be directly pathogenic. Neuropil aggregates have not yet been described in SCA3. We performed a systematic immunohistochemical study of serial thick sections through brains of seven clinically diagnosed and genetically confirmed SCA3 patients. Using antibodies against ataxin-3, p62, ubiquitin, the polyglutamine marker 1C2 as well as TDP-43, we analyzed neuronal localization, composition and distribution of aggregates within SCA3 brains. The analysis revealed widespread axonal aggregates in fiber tracts known to undergo neurodegeneration in SCA3. Similar to neuronal nuclear inclusions, the axonal aggregates were ubiquitinated and immunopositive for the proteasome and autophagy associated shuttle protein p62, indicating involvement of neuronal protein quality control mechanisms. Rare TDP-43 positive axonal inclusions were also observed. Based on the correlation between affected fiber tracts and degenerating neuronal nuclei, we hypothesize that these novel axonal inclusions may be detrimental to axonal transport mechanisms and thereby contribute to degeneration of nerve cells in SCA3.

Keywords

Ataxin-3 Axonal aggregates Polyglutamine diseases Protein aggregates SCA3