Biology subjects

Chatzi, A.

Publications and source records attributed to Chatzi, A..

3 recordsLinked to original sources

bioRxiv2021

A Thioredoxin reductive mechanism balances the oxidative protein import pathway in the intermembrane space of mitochondria

Mitochondria biogenesis crucially depends on the oxidative folding system in the mitochondrial intermembrane space. The oxidative capacity needs however to be balanced by a reductive pathway for optimal mitochondrial fitness. Here we report that the cytosolic thioredoxin machinery fulfils this critical reductive function by dual localisation in the mitochondrial intermembrane space (IMS) via an unconventional import pathway. We show that the presence of the Thioredoxin system in the IMS mediates a hitherto unknown communication between mitochondria biogenesis and the metabolic state of the cell via the cytosolic pool of NADPH. By a combination of complete in vitro reconstitution with purified components, import assays and protein interaction analysis we find that the IMS-localised thioredoxin machinery critically controls the redox state of Mia40, the key player in the MIA pathway in mitochondria thereby ensuring optimal mitochondria biogenesis. Intriguingly, we find that the IMS thioredoxin system fulfils a previously unknown role in the retrograde release of structurally destabilised proteins into the cytosol and protection against oxidative damage, both of which serve as critical mechanisms of mitochondrial surveillance and quality control.

biochemistry↗

bioRxiv2019

Genetic overlap between psychiatric disorders and neuropsychiatric symptoms in HD

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized exam of motor control and often presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown. We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders, and of intelligence, and testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n=5160) of HD patients. Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence. In general, polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.

genetics↗

bioRxiv2019

Huntington's disease onset is determined by length of uninterrupted CAG, not encoded polyglutamine, and is modified by DNA maintenance mechanisms

The effects of variable, glutamine-encoding, CAA interruptions indicate that a property of the uninterrupted HTT CAG repeat sequence, distinct from huntingtins polyglutamine segment, dictates the rate at which HD develops. The timing of onset shows no significant association with HTT cis-eQTLs but is influenced, sometimes in a sex-specific manner, by polymorphic variation at multiple DNA maintenance genes, suggesting that the special onset-determining property of the uninterrupted CAG repeat is a propensity for length instability that leads to its somatic expansion. Additional naturally-occurring genetic modifier loci, defined by GWAS, may influence HD pathogenesis through other mechanisms. These findings have profound implications for the pathogenesis of HD and other repeat diseases and question a fundamental premise of the "polyglutamine disorders".

genetics↗