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

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 v...

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Published in:Movement disorders 2018-12, Vol.33 (12), p.1961-1965
Main Authors: Niccolini, Flavia, Mencacci, Niccolo E., Yousaf, Tayyabah, Rabiner, Eugenii A., Salpietro, Vincenzo, Pagano, Gennaro, Balint, Bettina, Efthymiou, Stephanie, Houlden, Henry, Gunn, Roger N., Wood, Nicholas, Bhatia, Kailash P., Politis, Marios
Format: Article
Language:English
Subjects:
Adenylate cyclase
ADYC5
Basal ganglia
Brain diseases
chorea
Computed tomography
Cyclic AMP
Dopamine
Dopamine transporter
Globus pallidus
Magnetic resonance imaging
Movement disorders
Mutation
Neostriatum
Parkinson's disease
parkinsonism
PDE10A
PET
Phosphodiesterase
Positron emission tomography
Single photon emission computed tomography
Substantia grisea
Substantia nigra
Thalamus
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Summary: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. © 2018 International Parkinson and Movement Disorder Society
ISSN:0885-3185
1531-8257
DOI:10.1002/mds.27523