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Mitochondrial genomics of amyotrophic lateral sclerosis

Grant number: 14/25602-6
Support type:Scholarships abroad - Research
Effective date (Start): August 01, 2015
Effective date (End): July 31, 2016
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Marcelo Ribeiro da Silva Briones
Grantee:Marcelo Ribeiro da Silva Briones
Host: James R Broach
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo, SP, Brazil
Local de pesquisa : Pennsylvania State University, United States  


Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disease and the most common, adult-onset, motor neuron disease. About 10% ALS is the familial form in which 15-20% of cases are ALS1, associated with mutations in superoxide dismutase 1 (SOD1) gene. Nine genes are known to carry ALS-causing mutations and 13 others are implicated in ALS pathogenesis. These 22 genes are nuclear encoded and although mitochondrial dysfunction has been associated with ALS, mutations in mitochondrial genomes have never been screened in ALS samples. Here we propose a one-year pilot project where mitochondrial genomes of SOD1 ALS transgenic mice (presymptomatic and symptomatic) will be sequenced to test the hypothesis that ALS mitochondrial mutation patterns are different in (1) spinal cord, (2) non-motor brain cortex and (3) peripheral blood cells. The rationale is that because inactivated SOD1 protein accumulates in ALS mitochondria and SOD1 is involved with metabolism of mutagenic reactive oxygen species (ROS), it is expected that somatic mitochondrial mutation patterns might differ between affected and non-affected tissues. In parallel, we plan to sequence the mitochondrial genomes of 100 human peripheral blood samples from the ALS collection of the Institute for Personalized Medicine (Penn State University) and compare with non-affected individuals. As a secondary objective, we plan to map mitochondrial epigenetic alterations (DNA methylation) in the human and mouse sample sets by bisulfite sequencing. The central idea is to verify whether inherited and somatic mitochondrial mutations and epigenetic alterations could be associated with specific types of ALS and hopefully, with the onset and prognosis of ALS. As a future perspective, we plan to obtain human ALS brain and spinal cord samples from the NICHD brain and tissue Bank (University of Maryland) to conduct the mitochondrial genome and epigenome analysis in human ALS nervous tissue.