PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology

Flavia Niccolini, Niccolo E. Mencacci, Tayyabah Yousaf, Eugenii A. Rabiner, Vincenzo Salpietro, Gennaro Pagano, Bettina Balint, Stephanie Efthymiou, Henry Houlden, Roger N. Gunn, Nicholas Wood, Kailash P. Bhatia, Marios Politis*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: Striatal cyclic adenosine monophosphate activity modulates movement and is determined from the balance between its synthesis by adenylate cyclase 5 (ADCY5) and its degradation by phosphodiesterase 10A (PDE10A). Objective: We assessed the integrity of striatocortical pathways, in vivo, in 2 genetic hyperkinetic disorders caused by ADCY5 and PDE10A mutations. Methods: We studied 6 subjects with PDE10A and ADCY5 mutations using [11C]IMA107 PET, [123I]FP-CIT Single-photon emission computed tomography (SPECT) and multimodal MRI to investigate PDE10A and dopamine transporter availability, neuromelanin-containing neurons, and microstructural white and gray matter changes, respectively. Results: We found that PDE10A and ADCY5 mutations were associated with decreased PDE10A expression in the striatum and globus pallidus, decreased dopamine transporter expression in the striatum, loss of substantia nigra neuromelanin-containing neurons, and microstructural white and gray matter changes within the substantia nigra, striatum, thalamus, and frontoparietal cortices. Conclusions: Our findings indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways.

Original languageEnglish (US)
Pages (from-to)1961-1965
Number of pages5
JournalMovement Disorders
Volume33
Issue number12
DOIs
StatePublished - Dec 2018

Keywords

  • ADYC5
  • PDE10A
  • PET
  • chorea
  • parkinsonism

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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