title: Axonal inclusions in spinocerebellar ataxia type 3.
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.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, University of Groningen, 9713 RB Groningen, The Netherlands. Kay_Seidel@gmx.de
authors.forename: Kay
authors.initials: K
authors.lastname: Seidel
authors.forename: Wilfred F A
authors.initials: WF
authors.lastname: den Dunnen
authors.forename: Christian
authors.initials: C
authors.lastname: Schultz
authors.forename: Henry
authors.initials: H
authors.lastname: Paulson
authors.forename: Stefanie
authors.initials: S
authors.lastname: Frank
authors.forename: Rob A
authors.initials: RA
authors.lastname: de Vos
authors.forename: Ewout R
authors.initials: ER
authors.lastname: Brunt
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.forename: Harm H
authors.initials: HH
authors.lastname: Kampinga
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000473:pathology / Q000648:ultrastructure*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000473:pathology*; D017827:Machado-Joseph Disease / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D010455:Peptides; D016875:tau Proteins; C097188:polyglutamine; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase