Objective: To study in vitro expression of circadian rhythm genes (CLOCK, BMAL) in fibroblasts and neural cells of SCA17 patients.

Background: Spinocerebellar Ataxia 17 (SCA17) is an autosomal dominant progressive disease that belongs to the class of polyglutamine disorders. SCA17 is caused by CAG/CAA repeat expansion in the TBP gene leading to a neurodegenerative disease which clinical phenotypes is highly variable, resembling conditions like parkinsonism, Alzheimer’s and Huntington’s disease [1]. It has been suggested that alterations of circadian rhythm can play a role in the pathogenesis of neurodegenerative disorders and, up to now, no clear evidence from cellular models are available [2].

Method: Dermal fibroblast derived from two symptomatic SCA 17 patients (the proband and his father) and one healthy control (HC) were reprogrammed into human induced pluripotent stem cells (iPSCs) through virus-free and feeder-free protocol [3]. iPSCs were investigated for CLOCK and BMAL expression, for mitochondrial function and oxidative stress markers.

Results: Compared to HC, fibroblasts from patients showed a deranged expression of circadian rhythm genes and a worst energetic metabolism, in accordance to the disease severity phenotype of the patient but not with the mutation size that was the same for both patients (i.e. 44 repeats).

Conclusion: The expression of genes related to circadian rhythm is known to play a role in many neurodegenerative disorders as well as in brain aging [2]. In this study we found out that the expression of CLOCK and BMAL gene and cellular metabolism in a SCA 17 iPSCs cellular model were impaired. Although both patients shared the same number of CAG/CAA-repeats, the proband had a worse clinical phenotype and his iPSCs showed a greater impairment of circadian rhythm genes expression. It can be speculated that circadian rhythm gene expression and their alteration in SCA17 could play, at least in part, and indipendent role in disease onset and progression with respect to the mutation lenght. This study highlights the pleiotropic role of circadian rhythm in neurodegeneration, however more studies are warranted to shed a light between the fascinating and poor understood TBP mutation of SCA17 and the circadian mechanism.

References: [1] Klockgether, T., Mariotti, C. & Paulson, H.L. Spinocerebellar ataxia. Nat Rev Dis Primers 5, 24 (2019) [2] Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K, Giasson BI, Weaver DR, Holtzman DM, Fitzgerald GA. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest. 2013 Dec;123(12):5389-400. [3] Rosati J, Ferrari D, Altieri F, et al. Establishment of stable iPS-derived human neural stem cell lines suitable for cell therapies. Cell Death Dis. 2018 Sep 17;9(10):937.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/circadian-rhythm-alterations-in-an-in-vitro-cellular-model-of-spinocerebellar-ataxia-type-17/