title: Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3).
abstract: OBJECTIVE
  A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions.
  
  
  METHODS
  We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB⁺¹.
  
  
  RESULTS
  The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB⁺¹ was present in a subset of neurones with NNI. A subset of UBB⁺¹-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI.
  
  
  CONCLUSIONS
  Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB⁺¹ staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.
authors.affiliation: Department of Pathology and Medical Biology, University Medical Centre Groningen, Groningen, the Netherlands. kay_seidel@gmx.de
authors.forename: K
authors.initials: K
authors.lastname: Seidel
authors.forename: M
authors.initials: M
authors.lastname: Meister
authors.forename: G J
authors.initials: GJ
authors.lastname: Dugbartey
authors.forename: M P
authors.initials: MP
authors.lastname: Zijlstra
authors.forename: J
authors.initials: J
authors.lastname: Vinet
authors.forename: E R P
authors.initials: ER
authors.lastname: Brunt
authors.forename: F W
authors.initials: FW
authors.lastname: van Leeuwen
authors.forename: U
authors.initials: U
authors.lastname: Rüb
authors.forename: H H
authors.initials: HH
authors.lastname: Kampinga
authors.forename: W F A
authors.initials: WF
authors.lastname: den Dunnen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D017827:Machado-Joseph Disease / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011149:Pons / Q000378:metabolism* / Q000473:pathology; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494647:DNAJB1 protein, human; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C479419:UBB protein, human; D025801:Ubiquitin