Objective: To characterize a newly generated mouse model of the movement disorder caused by PDE10A pathogenic mutation F300L.

Background: Phosphodiesterase 10A (PDE10A) is a striatal specific enzyme that regulates dopaminergic and adenosinergic signaling in striatal projecting neurons through modulation of the intracellular levels of cAMP and cGMP. Heterozygous missense mutations in the GAF-B regulatory domain of PDE10A, including the recurrent variant F300L, were recently identified in patients with childhood-onset chorea and bilateral striatal MRI abnormalities. However, the mechanisms whereby these mutations cause abnormal movement production and striatal abnormalities are not known.

Method: A knock-in (KI) mouse model of the PDE10A F300L mutation was generated using CRISPR/Cas9 technology. Open Field and Rotarod were used to assess the motor phenotype of mice with heterozygous and homozygous PDE10A F300L. Biochemical and histopathological analyses of striata were performed by immunohistochemistry (IHC), immunofluorescence (IF) and western blot (WB).

Results: Behavioral phenotyping performed at 3, 6, and 12 months of age revealed that mice with the PDE10A-F300L had progressive motor abnormalities, including reduced spontaneous locomotion and reduced motor learning. Furthermore, WB and IHC showed reduced striatal PDE10A protein levels in mutant mice, accompanied by formation of cytosolic protein aggregates that stained positive for PDE10A. Histological analysis with Hematoxylin and Eosin and Nissl staining revealed prominent and progressive vacuolar lesions within the striatum beginning at one month of age. Finally, we observed severe and progressive astrocytosis in the striata of mutant mice but no significant microgliosis. Importantly, homozygous mice showed significantly more profound abnormalities than heterozygous mice, indicating a dosage effect of the mutation.

Conclusion: The motor abnormalities and profound striatal histopathological lesions of our mouse model suggest a parallel to that of MRI abnormalities and motor symptoms seen in patients harboring dominant PDE10A mutations. Insights revealing a reduction of PDE10A levels and protein aggregate formation in vivo, highlight the need to further characterize the pathophysiological mechanisms underlying PDE10A mutations in the GAF-B domain.

References: Mencacci NE, Kamsteeg EJ, Nakashima K, et al. De Novo Mutations in PDE10A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions. Am J Hum Genet. 2016 Apr 7;98(4):763-71. doi: 10.1016/j.ajhg.2016.02.015. PMID: 27058447; PMCID: PMC4833291. Niccolini F, Mencacci NE, Yousaf T, et al. PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology. Mov Disord. 2018 Dec;33(12):1961-1965. doi: 10.1002/mds.27523. Epub 2018 Oct 21. PMID: 30345538. Tejeda GS, Whiteley EL, Deeb TZ et al. Chorea-related mutations in PDE10A result in aberrant compartmentalization and functionality of the enzyme. Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):677-688. doi: 10.1073/pnas.1916398117. Epub 2019 Dec 23. PMID: 31871190; PMCID: PMC6955301.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/characterization-of-a-mouse-model-of-pde10a-related-autosomal-dominant-movement-disorder/