SCA28 is an autosomal dominant ataxia associated with AFG3L2 gene mutations. We performed a whole genome expression profiling using lymphoblastoid cell lines (LCLs) from four SCA28 patients, and six unrelated healthy controls matched for sex and age. We found 66 genes whose expression was statistically different, 35 of which were up-regulated (Fold Change - FC = 2.5-10) and 31 down-regulated (FC = 0.1-0.3). The differentially expressed genes were clustered in five functional categories: (1) regulation of cell proliferation; (2) regulation of programmed cell death; (3) response to oxidative stress; (4) cell adhesion, and (5) chemical homeostasis. To validate these data, we performed functional experiments that proved an impaired SCA28 LCLs growth compared to controls (p < 0.005), an increased number of cells in the G0/G1 phase (p < 0.001), and an increased mortality of patients' cells due to apoptosis (p < 0.05). We also showed that respiratory chain activity and reactive oxygen species levels were not altered, although lipid peroxidation in SCA28 LCLs was increased in basal conditions (p < 0.05). We did not detect mitochondrial DNA large deletions. An increase of TFAM, a crucial protein for mtDNA maintenance, and a decrease of DRP1, a key regulator of mitochondrial dynamic mechanism, suggested an alteration of mitochondrial network pathways. In conclusion, whole genome expression profiling in SCA28 LCLs allowed the identification of several altered pathways that may be related to the disease.
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