Objective: We aimed to identify sensitive and specific molecular markers of the cerebellar Purkinje neuron loss in Ataxia Teleangiectasia.

Background: Ataxia teleangiectasia is an autosomal recessively inherited disorder with loss of cerebellar Purkinje neurons and a deficient immune defense. The causative loss-of-function mutations in the Ataxia-Teleangiectasia-Mutated (ATM) gene hinder the repair of DNA-damage events. The corresponding mouse model with Atm-knock-out dies around the age of 4-6 months due to thymic lymphomas, without showing histological or behavioral signs of cerebellar damage.

Methods: We assessed a number of molecular markers of cerebellar Purkinje neuron loss, which were previously defined in the autosomal dominantly inherited Spinocerebellar Ataxia type 2 (SCA2) cerebellar tissue from patient autopsies and mouse models. As a sensitive detection method with near-linear correlation, quantitative reverse-transcriptase polymerase chain reaction was employed to measure the expression of candidate factor expression. Tata-binding-protein (Tbp) mRNA was used as loading control.

Results: Two known markers of cerebellar Purkinje neurons, Calbindin-1 (Calb1) and Inositol-Tris-Phosphate-Receptor-1 (Itpr1) showed significant reductions to 80% expression of the respective transcripts already at age 3 months (n = 8 KO vs 8 WT). Additional analyses of Reelin pathway components and DNA-damage markers are ongoing. Different ages and a comparison of homozygotes with heterozygotes are under study, to define the usefulness of these molecules as progression markers. 

Conclusions: Our identification of two calcium homeostasis factors as pre-symptomatic molecular markers of cerebellar Purkinje neuron loss will be useful to assess the neuroprotective potential of novel therapeutic approaches, such as bone marrow transplantation and anti-oxidative drugs.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/ataxia-teleangiectasia-mutated-knock-out-mouse-cerebellum-shows-significant-reduction-of-calcium-homeostasis-factors/