title: Cystatin C is differentially involved in multiple system atrophy phenotypes.
abstract: OBJECTIVE
  As cystatin C (CysC) is involved in some forms of neurodegeneration, we investigated the possible relationship between CysC and multiple system atrophy (MSA), including its parkinsonian (MSAp) and cerebellar (MSAc) phenotypes.
  
  
  METHODS
  Cystatin C gene (CST3) haplotypes were determined by PCR followed by KspI digestion in 50 MSA patients and 108 controls. CST3 and cathepsins B, D and L1 mRNA levels were studied in frozen post-mortem caudate nucleus and cerebellar samples of eight MSAp, four MSAc and 18 control brains and analysed by the ΔΔCt method. CysC immunohistochemistry was performed on three MSAp, three MSAc and three control cerebella. Additionally, determination of CST3 and cathepsins B, D and L1 mRNA levels and immunohistochemistry for CysC were carried out in cerebella from three patients with paraneoplastic cerebellar degeneration, three with spinocerebellar ataxia (type 3, SCA3) and three with cerebellar ischaemia (CI).
  
  
  RESULTS
  In the set of blood samples, the CST3 B-haplotype was associated with MSAp (OR 4.86, confidence interval 1.84-13.3). High CST3 mRNA levels were found in MSAp caudate nuclei [expression change: 3.08 (2.98-3.18)] and MSAc cerebella [expression change: 2.44 (2.14-2.88)]. In the latter there was CysC over-expression in Purkinje cells, Bergmann glia and dentate nucleus neurones. No cathepsin increase was detected in MSA cerebella. High mRNA levels of CST3 and cathepsins B and L1 were observed in SCA3 and CI brains.
  
  
  CONCLUSIONS
  CysC changes are differentially present in the parkinsonian and cerebellar forms of MSA and may play an important role in the pathogenesis of this neurodegenerative condition.
authors.affiliation: Servicio de Anatomía Patológica, Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Aintzane
authors.initials: A
authors.lastname: Urbizu
authors.affiliation: Servicio de Anatomía Patológica, Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Canet-Pons
authors.affiliation: Servicio de Anatomía Patológica, Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Munoz-Marmol
authors.affiliation: Pathology Department, Hospital Clínic Barcelona, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Iban
authors.initials: I
authors.lastname: Aldecoa
authors.affiliation: Servicio de Anatomía Patológica, Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Lopez
authors.affiliation: Unitat de Parkinson i Trastorns del Moviment, Servicio de Neurología, Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic/IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Yaroslau
authors.initials: Y
authors.lastname: Compta
authors.affiliation: Servicio de Neurología, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Alvarez
authors.affiliation: Servicio de Neurología, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ispierto
authors.affiliation: Unitat de Parkinson i Trastorns del Moviment, Servicio de Neurología, Centro de Investigación en Red de Enfermedades Neurodegenerativas (CIBERNED), Hospital Clínic/IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tolosa
authors.affiliation: Servicio de Anatomía Patológica, Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.|Universidad Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Ariza
authors.affiliation: Servicio de Anatomía Patológica, Instituto de Investigación en Ciencias de la Salud Germans Trias i Pujol, Hospital Universitario Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Katrin
authors.initials: K
authors.lastname: Beyer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D002421:Caudate Nucleus / Q000378:metabolism; D002526:Cerebellar Diseases / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D055316:Cystatin C / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000235:genetics* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D055316:Cystatin C; D012333:RNA, Messenger; C533912:CTSB protein, human; D002401:Cathepsin B; C533922:CTSD protein, human; D002402:Cathepsin D
keywords: MSA phenotype; cathepsin B expression; cathepsin D expression; cathepsin L1 expression; cystatin C expression; multiple system atrophy (MSA)