by In a groundbreaking study, scientists at the Max Planck Florida Institute for Neuroscience have made a significant discovery regarding the molecular mechanisms underlying memory formation. The researchers have identified a molecular anchor called VAP (vesicle-associated membrane protein-associated protein) that plays a crucial role in stabilizing mitochondria near synapses, enabling efficient energy supply during synaptic remodeling. These findings not only shed light on the processes that power memories but also open up new avenues for research into the pathology of neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis).
Synaptic plasticity, the dynamic remodeling of neuronal connections, is essential for learning and adaptation. However, these processes heavily rely on energy, which is where mitochondria come into play. Mitochondria, often referred to as biological batteries, reside close to sites of synaptic remodeling to ensure a local and efficient energy supply. Until now, the mechanism that anchors mitochondria near synapses has remained unknown.
To investigate this phenomenon, the research team employed an unbiased approach, utilizing advanced proteomics and a chemogenetic tool to identify proteins that potentially serve as anchors for dendritic mitochondria. Of the over 100 proteins initially identified, only a handful showed an ability to interact with the actin cytoskeleton, a network of protein filaments involved in synaptic structure remodeling.
Further experimentation revealed that when the VAP protein was genetically removed from neurons, mitochondrial stability was compromised. Without VAP, the interaction between mitochondria and the actin cytoskeleton was reduced, leading to the drifting of mitochondria away from synapses over time. Additionally, dendritic mitochondria became shorter and destabilized. This loss of mitochondrial stability had a significant impact on synaptic plasticity, impairing the ability of synapses to undergo structural and functional remodeling during memory formation.
The implications of this discovery extend beyond understanding the fundamental processes of memory formation. VAP mutations have been associated with ALS, a neurodegenerative disease characterized by the degeneration of motor neurons. The identification of VAP as a molecular anchor provides new insights into the pathological mechanisms of ALS and suggests that mitochondrial stability and energy support for plasticity may play a role in disease progression.
Dr. Vidhya Rangaraju, lead scientist of the study and research group leader at the Max Planck Florida Institute, highlights the significance of these findings and the direction of future research. The team plans to investigate the cellular mechanisms underlying cognitive symptoms frequently observed alongside motor symptoms in ALS, an area that has received limited attention thus far. The tools and approaches developed in this study will likely pave the way for a better understanding of neurodegenerative diseases and potentially uncover shared mechanisms of neurodegeneration in ALS and other neurological disorders.
The study’s first author, Ojasee Bapat, emphasizes the uniqueness of dendritic mitochondrial stability, pointing out that mitochondrial mobility in neuronal axons is considerably higher. While this research focused on the stabilization of dendritic mitochondria, the findings have broader implications for understanding the energetic support required for neuronal function across the entire brain.
The discovery of VAP as a molecular anchor presents a major breakthrough in the field of neuroscience and neurodegenerative disease research. By elucidating the mechanisms behind mitochondrial stabilization and energy availability, this study provides valuable insights into the processes that underlie memory formation and their potential implications for neurodegeneration. With further research, these findings may contribute to the development of novel therapeutic strategies for ALS and other neurological disorders.
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1.Source: Coherent Market Insights, Public sources, Desk research
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