Project description:Many observations suggest that mutations of mtDNA could be responsible of the neurodegenerative changes associated with AD. We examined the signal intensity of the four alleles for each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls utilizing a resequencing array, the MitoChip v2.0, and identified 275 statistically different nps which all, with the exception of one, showed an increased contribution of non-reference alleles for AD patients. PCA and cluster analysis showed that 5 of these nps, characterized by low-level heteroplasmy, could discriminate AD from control subjects with 80% of cases correctly classified.
Project description:Many observations suggest that mutations of mtDNA could be responsible of the neurodegenerative changes associated with AD. We examined the signal intensity of the four alleles for each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls utilizing a resequencing array, the MitoChip v2.0, and identified 275 statistically different nps which all, with the exception of one, showed an increased contribution of non-reference alleles for AD patients. PCA and cluster analysis showed that 5 of these nps, characterized by low-level heteroplasmy, could discriminate AD from control subjects with 80% of cases correctly classified. This study included a total of 18 AD patients and 18 age-matched controls. Data acquisition was performed using the Affymetrix Genechip Command Console (AGCC) software and data analysis was carried out with GSEQ 4.1.
Project description:Mitochondrial DNA (mtDNA) damage is considered as a possible primary cause of Parkinson’s disease (PD). To explore the issue, mtDNA sequences from whole blood were analyzed in PD patients and controls using a resequencing chip and allelic substitutions were estimated for each nucleotide position (np) along the entire mtDNA sequence. Overall, 58 np showed a different allelic distribution in the two groups; of these, 81% showed an increase of non-reference alleles in PD patients, similar to findings reported in patients with Alzheimer’s disease, albeit in reduced proportion. These results suggest that age-related neurodegenerative diseases could share a mechanism involving mtDNA.
Project description:Z-DNA is a non-canonical structure capable of activating innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated detection of Z-DNA in Alzheimer's disease (AD) remains poorly defined. Here, we found that ZBP1 is amplified in AD microglia, triggering innate immune response and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that fragmented oxidized mtDNA (Ox-mtDNA), produced during oxidative stress, cleaved by mitochondria nucleases, and released via the mPTP-VDAC channel, serves as the source of Z-form mtDNA. We demonstrated that Z-DNA-activated ZBP1 engages RIPK1, promoting RIPK1 kinase activation and RIPK1-kinase dependent transcription of pro-inflammatory molecules and intracellular inflammatory signaling mediators for various inflammatory pathways. Deletion of ZBP1 or genetic inhibition of RIPK1 kinase limits the innate immune response, neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings demonstrate that innate immune signaling by Z-form mtDNA-ZBP1-RIPK1 axis drives microglia-mediated neuroinflammation in AD, providing new insights into the immune mechanisms underlying AD pathogenesis and revealing a potential therapeutic avenue for AD.
Project description:Currently there is no treatment for mitochondrial disease, a group of devastating inherited disorders caused by mutations in mitochondrial DNA (mtDNA). Here we report a strategy to prevent the germline transmission of mitochondrial diseases. This technique is based on the specific elimination of mutated mtDNA through the use of mitochondria targeted nucleases. Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. A total of 4 samples were analyzed. Test samples were compared to sex-matched reference samples.
Project description:Analysis of RISC bound short (s)RNAs in various cell lines and mouse models of Alzheimer's disease and in human AD patients reveals a contribution of 6mer seed toxicity to the neurotoxicity associated with AD
Project description:Analysis of RISC bound short (s)RNAs in various cell lines and mouse models of Alzheimer's disease and in human AD patients reveals a contribution of 6mer seed toxicity to the neurotoxicity associated with AD
Project description:Analysis of RISC bound short (s)RNAs in various cell lines and mouse models of Alzheimer's disease and in human AD patients reveals a contribution of 6mer seed toxicity to the neurotoxicity associated with AD
Project description:Analysis of RISC bound short (s)RNAs in various cell lines and mouse models of Alzheimer's disease and in human AD patients reveals a contribution of 6mer seed toxicity to the neurotoxicity associated with AD
Project description:Analysis of RISC bound short (s)RNAs in various cell lines and mouse models of Alzheimer's disease and in human AD patients reveals a contribution of 6mer seed toxicity to the neurotoxicity associated with AD
