Validation of new TGFB1/SMAD3 mutations associated with Parkinson’s disease with dementia patients

We have previously shown that Smad3 deficiency induces parkinsonism in mice, characterized by postnatal dopaminergic neurodegeneration, catabolism of striatal dopamine and the presence of -synuclein aggregates in neuronal bodies and neurites, with similarities to Lewy bodies of Parkinson’s disease (PD) patients. In addition, Smad3 null mice present motor and cognitive alterations (Tapia-González et al. 2011 y 2013; Giráldez-Pérez et al. 2014; Muñoz et al. 2016). We recently performed 2 independent genetic association studies to search for genetic variants in 6 genes of the TGFb / Smad intracellular signaling pathway that could be associated with PD. Through next-generation sequencing, via Ion Torrent, we analysed the nucleotide sequences of the genes TGFB1, TGFB2, SMAD3, SMAD2, TGFBR1, and TGFBR2 in their exons, 5’UTR, 3’UTR regions, and splicing zones. For these studies, samples of PD patients with dementia were used, obtained from the Spanish National DNA Bank – ISCIII (AL-14-0008). A first phase of discovery was made (70 cases and 62 controls) and a second phase with exact replication using new patients (71 cases and 73 controls), in which a total of 422 genetic variants were detected, of which 155 are new. The association analysis discovered 2 genetic variants associated with PD. In addition, epistasis studies suggest a possible interaction between both genetic variants to increase or decrease the risk of developing PD (data submitted). We have recently developed a PCR-RFLP detection system for both mutations and in the present proposal we want to analyse these mutations in PD patients without dementia and Alzheimer’s disease (AD) patients, in order to better characterize the association of these variants with PD or with dementias such as those present in PD and AD.