Poirier A, Picard C, Labonté A, Aubry I, Auld D, Zetterberg H, Blennow K, PREVENT-AD research group, Tremblay ML, Poirier J. PTPRS is a novel marker for early Tau pathology and synaptic integrity in Alzheimer's disease. Sci Rep. 2024 Jun 26;14(1):14718. PubMed.
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I'd like to offer an alternative data interpretation for “PTPRS is a novel marker for early Tau pathology and synaptic integrity in Alzheimer's disease.”
The discovery of a new gene associated with AD is rather exciting. The data in Figures 3, 4A, and 6 convincingly showed that the major allele (T) of PTPRS, rs10415488, might increase AD biomarkers, whereas the minor allele (C) could offer protection.
However, the data do not provide strong support for the conclusion that rs10415488 effects on AD are simply due to the difference of PTPRS expression level. Instead, other potential effects of genetic variants, such as functional alteration due to changed splicing, should be taken into consideration. It remains an open question what role this gene plays in Alzheimer's disease and how it interacts with ApoE4.
Are the expression levels sufficient to explain PTPRS's connection to AD?
The mRNA levels across the TT, CT, and CC genotypes in Figure 1A do not appear to differ significantly, making it less likely to fully account for the AD association observed in Figures 3, 4A, and 6. It would be nice for the authors to show the R² values in Figure 1A, as they are crucial for evaluating the strength of the relationship between variables. For example, if the R² values are similar to the one in Supplemental Figure 1 (R²= 0.04), then it's worth considering what other aspects of this SNP might contribute to AD association—could functional alterations be the underlying reason? Could the minor allele (C) lead to a loss of function or gain of function in PTPRS, thereby providing protection against AD?
Regarding ApoE4 stratification, if the difference in PTPRS expression is observed only in the ApoE4-positive group (as shown in Figure 1B), but not in the ApoE4 negative group or without stratification, then that would suggest a potential interaction between ApoE4 and PTPRS, marking a notably interesting discovery. However, these data are not sufficient evidence for a broad conclusion on how PTPRS expression impacts AD, especially when viewed alongside the regression analysis (in Figure 5) in the ApoE4-positive group, which shows no correlation between AD biomarkers and PTPRS levels, with R² values near zero and p-values not significant. For the ApoE4-negative group in Figure 5, the authors claimed that T-tau and P-tau “displayed significant associations” with PTPRS, but once again, with the R² and p values given in the figure, it's a stretch to assert a meaningful association.
Overall, the data provided in this article did indicate a connection between the PTPRS SNP and AD, but it is premature to attribute the disease association to the level of gene expression.
Positive or negative impact on synaptic integrity?
The authors stated in the abstract that "PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1," yet described in Figure 2 a negative correlation with SYT-1 and a positive correlation with SNAP25. If both are considered markers of synaptic integrity, how do the authors reconcile these opposing trends? Is higher PTPRS level associated with better or worse synaptic integrity? It would also be beneficial if the authors could discuss how these findings align with their previous animal studies, which indicated increased synaptic density in neurons lacking PTPRS (Horn et al., 2012).
AD association possibly explained by altered splicing or structural-functional changes?
The PTPRS gene has many alternative splicing isoforms, which predominantly affect the domains in its extracellular segment (Coles et al., 2015). It is plausible that the position of this SNP may predispose it to influence splicing patterns, potentially altering protein folding and function. Hence it would be valuable to investigate how the T and C alleles impact PTPRS function. In a scenario where the protective minor allele (C) leads to a loss of function, this could reconcile the findings of this study with otherwise conflicting studies, including the authors' earlier work and the human brain datasets mentioned in the discussion.
Until we have that information, it's premature to determine whether PTPRS is protective or detrimental.
References:
Horn KE, Xu B, Gobert D, Hamam BN, Thompson KM, Wu CL, Bouchard JF, Uetani N, Racine RJ, Tremblay ML, Ruthazer ES, Chapman CA, Kennedy TE. Receptor protein tyrosine phosphatase sigma regulates synapse structure, function and plasticity. J Neurochem. 2012 Jul;122(1):147-61. Epub 2012 May 17 PubMed.
Coles CH, Jones EY, Aricescu AR. Extracellular regulation of type IIa receptor protein tyrosine phosphatases: mechanistic insights from structural analyses. Semin Cell Dev Biol. 2015 Jan;37:98-107. Epub 2014 Sep 16 PubMed.
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