Periodic Reporting for period 2 - AxoMyoGlia (Spatio-functional cellular interplay in peripheral nerve diseases)
Período documentado: 2022-07-01 hasta 2023-12-31
Neuromuscular disorders represent prevalent neurological conditions characterized by compromised motor function. These disorders involve various cell types within the neuromuscular unit, including motoneurons and their axons, glial cells, as well as muscle cells. Although these components are closely interconnected, the precise mechanisms dictating their interaction and giving rise to disease progression remain poorly understood. The AxoMyoGlia project seeks to unveil the molecular interactions and spatial relationships among these critical cellular constituents.
As we delve into this project, we are focusing on using peripheral neuropathies as a model system. Our goal is to figure out how glial dysfunction affects axonal function and how these effects spread throughout the neuromuscular unit. Essentially, we are curious to understand how problems in glial cells can trigger issues not only in axons but also in muscle cells and the spinal cord, leading to the progression of these disorders. To achieve this, we are employing advanced imaging techniques and are working with mouse models to create a comprehensive map of the molecular interactions that occur within the neuromuscular unit. This way, we hope to shed light on how glial and axonal dysfunction collaborate to drive the disease process.
One fascinating aspect we recently observed is that even though glial mutations are present throughout the peripheral nervous system, the onset and development of glial pathology are uneven across the nerve. This non-uniformity is a major contributor to the diverse ways these disorders manifest, including axonal degeneration and muscle atrophy. Our project also has a unique angle where we are trying to decipher the spatial patterns of glial and axonal dysfunction along the nerve and their relationship with changes at the neuromuscular junction.
Our objectives in the AxoMyoGlia project are to build a holistic understanding of how different cells interact within the neuromuscular unit, untangle the roles that glial and axonal dysfunction play in the disease process, and examine the effects of these dysfunctions on the neuromuscular junction. If we can accomplish these goals, we are hopeful that our research will uncover fundamental shared mechanisms that underlie neuromuscular disorders. Ultimately, we are aiming to contribute to the development of more effective treatments for these conditions that currently lack satisfactory therapeutic options.
As we delve into this project, we are focusing on using peripheral neuropathies as a model system. Our goal is to figure out how glial dysfunction affects axonal function and how these effects spread throughout the neuromuscular unit. Essentially, we are curious to understand how problems in glial cells can trigger issues not only in axons but also in muscle cells and the spinal cord, leading to the progression of these disorders. To achieve this, we are employing advanced imaging techniques and are working with mouse models to create a comprehensive map of the molecular interactions that occur within the neuromuscular unit. This way, we hope to shed light on how glial and axonal dysfunction collaborate to drive the disease process.
One fascinating aspect we recently observed is that even though glial mutations are present throughout the peripheral nervous system, the onset and development of glial pathology are uneven across the nerve. This non-uniformity is a major contributor to the diverse ways these disorders manifest, including axonal degeneration and muscle atrophy. Our project also has a unique angle where we are trying to decipher the spatial patterns of glial and axonal dysfunction along the nerve and their relationship with changes at the neuromuscular junction.
Our objectives in the AxoMyoGlia project are to build a holistic understanding of how different cells interact within the neuromuscular unit, untangle the roles that glial and axonal dysfunction play in the disease process, and examine the effects of these dysfunctions on the neuromuscular junction. If we can accomplish these goals, we are hopeful that our research will uncover fundamental shared mechanisms that underlie neuromuscular disorders. Ultimately, we are aiming to contribute to the development of more effective treatments for these conditions that currently lack satisfactory therapeutic options.
We successfully established single-cell RNA sequencing via the iCell8 platform and collected various data sets from nervous tissue that are currently being extended and analysed. This includes the interrelation with morphological data and spatial transcriptomic approaches. In addition, we established whole tissue clearing and imaging, 3D electron microscopy and in vivo mitotracking. A manuscript with a focus on single cell transcriptomics is envisioned for submission by the end of 2023.
Given the enormous relevance of events of demyelination, particularly concerning immune-related mechanisms, within the central nervous system (CNS), we have chosen to align our investigations in the peripheral nervous system (PNS) by examining analogous mechanisms in the CNS. Importantly, our study of autoimmune demyelination in multiple sclerosis and its associated models has led us to identify myelin insulation itself as a contributor to axonal integrity. Intriguingly, we found that it's not the demyelination process itself, but rather the continued myelin sheathing by impaired oligodendrocytes, that undermines their support function for axons. This situation represents a unique risk for axonal survival (Schäffner and Bosch-Queralt et al., Nature Neuroscience 2023). Currently, we are expanding upon these discoveries to comprehend the role of Schwann cells in maintaining axonal function in the context of both immune and non-immune-related glial dysfunction in neuropathies.
In conclusion, AxoMyoGlia's systematic advancements shed light on the complex pathomechanisms in myelin diseases. Notably, the identification of myelin insulation as a risk factor for axonal integrity open novel therapeutic strategies for these common neurological disorders.
Given the enormous relevance of events of demyelination, particularly concerning immune-related mechanisms, within the central nervous system (CNS), we have chosen to align our investigations in the peripheral nervous system (PNS) by examining analogous mechanisms in the CNS. Importantly, our study of autoimmune demyelination in multiple sclerosis and its associated models has led us to identify myelin insulation itself as a contributor to axonal integrity. Intriguingly, we found that it's not the demyelination process itself, but rather the continued myelin sheathing by impaired oligodendrocytes, that undermines their support function for axons. This situation represents a unique risk for axonal survival (Schäffner and Bosch-Queralt et al., Nature Neuroscience 2023). Currently, we are expanding upon these discoveries to comprehend the role of Schwann cells in maintaining axonal function in the context of both immune and non-immune-related glial dysfunction in neuropathies.
In conclusion, AxoMyoGlia's systematic advancements shed light on the complex pathomechanisms in myelin diseases. Notably, the identification of myelin insulation as a risk factor for axonal integrity open novel therapeutic strategies for these common neurological disorders.
The insights into the spatio-functional cellular interplay in peripheral neuropathies and myelin diseases obtained within the framework of this project will help to identify new therapeutic targets and strategies for patients affected by these common neurological disorders.