Role of a novel variant of SQSTM1 gene in neurodegeneration
Neurological disorders are often associated with variation in the genes. Here, a case study on a 20 year old Indian male with neurodegenerative disorder linked with novel mutation in the SQSTM1. The patient presented with the symptoms such as ataxia, abnormal downgaze, ADHD, and cognitive impairment. Dr. Faruq and his group performed a whole-exome sequencing identified a homozygous insertion variant in the SQSTM1 gene, leading to premature truncation of protein.
They also derive the lymphoblastoid cell lines from the patient and parent to investigate the molecular effect of the mutation. Analysis revealed complete absence of SQSTM1/p62 protein, impaired autophagy flux, increased ROS and mitochondrial dysfunction. In the patient drive cells mitochondrial dynamics were disrupted, which changes the shape, size, number, membrane potential and ATP synthesis as compared to controls.
This study highlights the molecular mechanism underlying SQSTM1 associated neurodegeneration and provides insights into potential therapeutic targets.
Cognitive Impairment, Ataxia, Dystonia, and Gaze Palsy Due to a Novel Variant in SQSTM1: New Lessons
Effect of moderate hyperhomocysteinemia on endothelial cells
Hyperhomocysteinemia (HHy) is a metabolic abnormality characterized by elevated levels of homocysteine, linked to various pathologies like cardiovascular disorders, neurological diseases, and kidney diseases. While severe HHy is associated with endothelial dysfunction
and cytotoxicity, the impact of moderate HHy, which is more commonly observed in the people, on endothelial dysfunction remains unclear.
This study investigated the effect of moderate HHy on endothelial dysfunction, using in vitro models of endothelial cells and an in vivo zebrafish model. The key finding of the study is moderate HHy impaired endothelial migration and proliferation, key processes in angiogenesis. They also report that moderate HHy did not affect canonical VEGF/VEGFR signaling or induces ROS instead they induced ER stress, leading to aberrant actin cytoskeleton remodeling and impaired migration. Furthermore, moderate HHy inhibits mitochondrial respiration and ATP production, and reduces the activity of mitochondrial complex IV.
In conclusion, moderate HHy adversely affects endothelial function by impairing migration and proliferation, mediated through adaptive UPR activation and metabolic rewiring.
Genome-wide transcriptomic and biochemical profiling of MDD
Major depressive disorder (MDD) is a prevalent psychiatric condition with significant impacts on quality of life and potential risks of suicidal thoughts if left untreated. Despite the availability of second-generation antidepressants (ADs), the majority of the patients do not respond to the treatment, highlighting the need for personalized medicines. Researchers identified various theories, including monoamine, neuroendocrine, neuroinflammation, and GABAergic theories.
In this study which is focused on the North Indian population, whole-genome transcriptomic changes associated with MDD susceptibility, symptom severity, and AD response were investigated. The study identified genes with altered expression patterns distinguishing MDD cases from healthy controls, with dysregulation in immune/inflammatory and apoptosis pathways. Additionally, they identified genes associated with distinct severity levels, between mild and severe cases. Revealing the potential involvement of pathways such as TNF-α – NF-κB – IL8 in modulating treatment outcomes.
In conclusion, the study provides valuable insights into the molecular mechanisms underlying MDD susceptibility, symptom severity, and treatment response in the Indian population. The identified gene expression signatures and biochemical associations contribute to our understanding of MDD pathogenesis and may inform personalized diagnostic and therapeutic strategies.