Your browser doesn't support javascript.
loading
In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3.
Costa, Maria do Carmo; Radzwion, Maria; McLoughlin, Hayley S; Ashraf, Naila S; Fischer, Svetlana; Shakkottai, Vikram G; Maciel, Patrícia; Paulson, Henry L; Öz, Gülin.
Afiliación
  • Costa MDC; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
  • Radzwion M; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
  • McLoughlin HS; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
  • Ashraf NS; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
  • Fischer S; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
  • Shakkottai VG; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
  • Maciel P; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
  • Paulson HL; Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal.
  • Öz G; Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
Mov Disord ; 35(10): 1774-1786, 2020 10.
Article en En | MEDLINE | ID: mdl-32621646
ABSTRACT

BACKGROUND:

No treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of disease pathology recapitulated by animal models.

OBJECTIVE:

We sought to identify shared in vivo neurochemical signatures in two mouse models of SCA3 that reflect the human disease pathology.

METHODS:

Cerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by in vivo magnetic resonance spectroscopy at 9.4 tesla. To validate the neurochemical biomarkers, levels of neurofilament medium (NFL; indicator of neuroaxonal integrity) and myelin basic protein (MBP; indicator of myelination) were measured in cerebellar lysates from a subset of mice and patients with SCA3. Finally, NFL and MBP levels were measured in the cerebellar extracts of Q84/Q84 mice upon silencing of the mutant ATXN3 gene.

RESULTS:

Both Q84/Q84 and Q135 mice displayed lower N-acetylaspartate than wild-type littermates, indicating neuroaxonal loss/dysfunction, and lower myo-inositol and total choline, indicating disturbances in phospholipid membrane metabolism and demyelination. Cerebellar NFL and MBP levels were accordingly lower in both models as well as in the cerebellar cortex of patients with SCA3 than controls. Importantly, N-acetylaspartate and total choline correlated with NFL and MPB, respectively, in Q135 mice. Long-term sustained RNA interference (RNAi)-mediated reduction of ATXN3 levels increased NFL and MBP in Q84/Q84 cerebella.

CONCLUSIONS:

N-acetylaspartate, myo-inositol, and total choline levels in the cerebellum are candidate biomarkers of neuroaxonal and oligodendrocyte pathology in SCA3, aspects of pathology that are reversible by RNAi therapy. © 2020 International Parkinson and Movement Disorder Society.
Asunto(s)
Palabras clave

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Enfermedad de Machado-Joseph Idioma: En Revista: Mov Disord Asunto de la revista: NEUROLOGIA Año: 2020 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Enfermedad de Machado-Joseph Idioma: En Revista: Mov Disord Asunto de la revista: NEUROLOGIA Año: 2020 Tipo del documento: Article