Axonal inclusions in spinocerebellar ataxia type 3

Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, 9713 RB Groningen, The Netherlands.
Acta Neuropathologica (Impact Factor: 10.76). 10/2010; 120(4):449-60. DOI: 10.1007/s00401-010-0717-7
Source: PubMed


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.

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Available from: Wilfred F.A. den Dunnen, Sep 30, 2015
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    • "Besides the hallmark lesion, e.g., the neuronal intranuclear inclusion (NII), diffuse nuclear staining, granular cytoplasmic staining, and neuritic staining may be observed (Figure 3). Other polyQ-diseases [like several of the spino-cerebellar ataxias (SCA), dentato-rubro-pallido-luysian atrophy (DRPLA), or HD-Like 2 (HDL2)] show similar staining patterns (Seidel et al., 2010, 2011). They can be differentiated however, based upon the variegated neuroanatomical degeneration throughout the nervous system and the density/neuroanatomical distribution of the different inclusion patterns (Seidel et al., 2012). "
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    • "A list of primary antibodies is supplied in the online Supplementary material . For more detailed methods, we refer to other publications (Seidel et al., 2010, 2012; Olah et al., 2012). A muscle biopsy was also taken from the quadriceps muscle (vastus lateralis on the right side). "
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    • "Ubiquitin-positive aggregates have been observed in axonal projections that are known to degenerate in SCA3 patients. It is likely that these aggregates are detrimental to axonal transport mechanisms; this however remains to be established (Seidel et al. 2010a). Similar evidence comes from animal models of Huntington's disease. "
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