Axonal inclusions in spinocerebellar ataxia type 3

Kay Seidel*, Wilfred F. A. den Dunnen, Christian Schultz, Henry Paulson, Stefanie Frank, Rob A. de Vos, Ewout R. Brunt, Thomas Deller, Harm H. Kampinga, Udo Rueb

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    72 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)449-460
    Number of pages12
    JournalActa Neuropathologica
    Volume120
    Issue number4
    DOIs
    Publication statusPublished - Oct-2010

    Keywords

    • Ataxin-3
    • Axonal aggregates
    • Polyglutamine diseases
    • Protein aggregates
    • SCA3
    • MACHADO-JOSEPH-DISEASE
    • NEURONAL INTRANUCLEAR INCLUSIONS
    • MULTIPLE SYSTEM ATROPHY
    • GLIAL INCLUSIONS
    • BRAIN-STEM
    • POLYGLUTAMINE DISEASES
    • PRECEREBELLAR NUCLEI
    • SCA3 PATIENTS
    • TAU-PROTEIN
    • BINDING

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