It is well known that amyloidogenic proteins (i.e., proteins that tend to misfold and then aggregate in insoluble deposits during disease) have a tendency to behave in a prion-like fashion. In other words, they function as seeds for the misfolding of protein counterparts leading to protein aggregation. In the current work, the development of a novel method to isolate and purify proteins that constitute aggregates contributing to TDP-43 proteinopathy is evidenced. The strength of this work lies in that, in combination with mass-spectrometry, the authors have started shedding light on the molecular differences across TDP pathological subtypes, specifically, FTLD-TDP-A and FTLD-TDP-C. The significance of this work is that these features could represent a means to discriminate across FTLD subtypes molecularly and that a molecular definition of the pathogenic process might indicate impacted sub-cellular (and cell-specific) pathways that lead to disease, opening a concrete opportunity to identify molecular targets that are specific to the different subtypes of the TDP-FTD spectrum.
Here the authors are able to describe the microenvironment around and within the pathological lesions at a scale of resolution that has not been reached before. And they have found consistent and robust patterns that allow them to link protein pathology to a specific clinical phenotype (i.e. FTLD-TDP A and C).
The contribution of this manuscript is twofold. First, we get to know a bit more about the molecular composition of subcellular lesions caused by or in association with TDP-43 pathology, as well as their associated cell-specificity. For example, it is noteworthy that aggregate elements such as FBXO2 locate to astrocytes and not to neurons. This study has shown the relationship (physical and functional) between TDP-43 and FBXO2 is possibly more complex than previously thought, but at the same time, may help better interpret it. Second, these adjunct proteins might prove to be novel potential genetic candidates if they harbor deleterious variants that act as disease modifiers or determine the specific pathological subtype affecting and impacting FTLD and ALS cases (with TDP-43 pathology). At the very least, they represent a stepping stone in deciphering differential cellular vulnerability and differential pathogenic mechanisms.
Clearly, and as the authors stated, it will need to be verified if the seeding capacity and strain propagation are conserved in vivo, since this is not a matter the current work is able to answer. As well, the conundrum of cause versus consequence remains open for debate: is the specific clinical manifestation the driving force leading to different aggregated protein species (we already know from in vitro studies that amyloid proteins tend to form different types of aggregates based on the chemico-physical and temporal features of the experimental conditions)? Or is it the other way around, i.e., is it the propensity of TDP-43 to aggregate as type A or type C that drives and differentiates the clinical phenotypes? In other words, are the aggregates a consequence of, or the determinant of, the clinical subtype?
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University College London
University of Reading
It is well known that amyloidogenic proteins (i.e., proteins that tend to misfold and then aggregate in insoluble deposits during disease) have a tendency to behave in a prion-like fashion. In other words, they function as seeds for the misfolding of protein counterparts leading to protein aggregation. In the current work, the development of a novel method to isolate and purify proteins that constitute aggregates contributing to TDP-43 proteinopathy is evidenced. The strength of this work lies in that, in combination with mass-spectrometry, the authors have started shedding light on the molecular differences across TDP pathological subtypes, specifically, FTLD-TDP-A and FTLD-TDP-C. The significance of this work is that these features could represent a means to discriminate across FTLD subtypes molecularly and that a molecular definition of the pathogenic process might indicate impacted sub-cellular (and cell-specific) pathways that lead to disease, opening a concrete opportunity to identify molecular targets that are specific to the different subtypes of the TDP-FTD spectrum.
Here the authors are able to describe the microenvironment around and within the pathological lesions at a scale of resolution that has not been reached before. And they have found consistent and robust patterns that allow them to link protein pathology to a specific clinical phenotype (i.e. FTLD-TDP A and C).
The contribution of this manuscript is twofold. First, we get to know a bit more about the molecular composition of subcellular lesions caused by or in association with TDP-43 pathology, as well as their associated cell-specificity. For example, it is noteworthy that aggregate elements such as FBXO2 locate to astrocytes and not to neurons. This study has shown the relationship (physical and functional) between TDP-43 and FBXO2 is possibly more complex than previously thought, but at the same time, may help better interpret it. Second, these adjunct proteins might prove to be novel potential genetic candidates if they harbor deleterious variants that act as disease modifiers or determine the specific pathological subtype affecting and impacting FTLD and ALS cases (with TDP-43 pathology). At the very least, they represent a stepping stone in deciphering differential cellular vulnerability and differential pathogenic mechanisms.
Clearly, and as the authors stated, it will need to be verified if the seeding capacity and strain propagation are conserved in vivo, since this is not a matter the current work is able to answer. As well, the conundrum of cause versus consequence remains open for debate: is the specific clinical manifestation the driving force leading to different aggregated protein species (we already know from in vitro studies that amyloid proteins tend to form different types of aggregates based on the chemico-physical and temporal features of the experimental conditions)? Or is it the other way around, i.e., is it the propensity of TDP-43 to aggregate as type A or type C that drives and differentiates the clinical phenotypes? In other words, are the aggregates a consequence of, or the determinant of, the clinical subtype?
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