Background Parkinson’s disease(PD)and multiple system atrophy(MSA)are classified asα-synucleinopathies and are primarily differentiated by their clinical phenotypes.Delineating these diseases based on their specific...Background Parkinson’s disease(PD)and multiple system atrophy(MSA)are classified asα-synucleinopathies and are primarily differentiated by their clinical phenotypes.Delineating these diseases based on their specificα-synuclein(α-Syn)proteoform pathologies is crucial for accurate antemortem biomarker diagnosis.Newly identifiedα-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity.This prompted the need for a comparative study focusing onα-Syn epitope-specific immunoreactivities in both diseases,which could clarify the extent of pathological overlap and diversity,and guide more accurate biomarker development.Methods We utilised a multiplex immunohistochemical approach to detect multiple structural domains ofα-Syn proteoforms across multiple regions prone to pathological accumulation in MSA(n=10)and PD(n=10).Comparison of epitope-specificα-Syn proteoforms was performed in the MSA medulla,inferior olivary nucleus,substantia nigra,hippocampus,and cerebellum,and in the PD olfactory bulb,medulla,substantia nigra,hippocampus,and entorhinal cortex.Results N-terminus and C-terminus antibodies detected significantly moreα-Syn pathology in MSA than antibodies for phosphorylated(pS129)α-Syn,which are classically used to detectα-Syn.Importantly,C-terminus immunolabelling is more pronounced in MSA compared to PD.Meanwhile,N-terminus immunolabelling consistently detected the highest percentage ofα-Syn across pathologically burdened regions of both diseases,which could be of biological significance.As expected,oligodendroglial involvement distinguished MSA from PD,but in contrast to PD,no substantial astrocytic or microglialα-Syn accumulation in MSA occurred.These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope.In comparison,N-terminus neuronalα-Syn was present in PD and MSA,with most MSA neurons lacking pS129α-Syn proteoforms.This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification ofα-Syn pathological load acrossα-synucleinopathies.Conclusions These findings underscore the necessity of utilising a multiplex approach to detectα-Syn,most importantly including the N-terminus,to capture the entire spectrum ofα-Syn proteoforms inα-synucleinopathies.The data provide novel insights toward the biological differentiation of theseα-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases.展开更多
文摘Background Parkinson’s disease(PD)and multiple system atrophy(MSA)are classified asα-synucleinopathies and are primarily differentiated by their clinical phenotypes.Delineating these diseases based on their specificα-synuclein(α-Syn)proteoform pathologies is crucial for accurate antemortem biomarker diagnosis.Newly identifiedα-Syn pathologies in PD raise questions about whether MSA exhibits a similar diversity.This prompted the need for a comparative study focusing onα-Syn epitope-specific immunoreactivities in both diseases,which could clarify the extent of pathological overlap and diversity,and guide more accurate biomarker development.Methods We utilised a multiplex immunohistochemical approach to detect multiple structural domains ofα-Syn proteoforms across multiple regions prone to pathological accumulation in MSA(n=10)and PD(n=10).Comparison of epitope-specificα-Syn proteoforms was performed in the MSA medulla,inferior olivary nucleus,substantia nigra,hippocampus,and cerebellum,and in the PD olfactory bulb,medulla,substantia nigra,hippocampus,and entorhinal cortex.Results N-terminus and C-terminus antibodies detected significantly moreα-Syn pathology in MSA than antibodies for phosphorylated(pS129)α-Syn,which are classically used to detectα-Syn.Importantly,C-terminus immunolabelling is more pronounced in MSA compared to PD.Meanwhile,N-terminus immunolabelling consistently detected the highest percentage ofα-Syn across pathologically burdened regions of both diseases,which could be of biological significance.As expected,oligodendroglial involvement distinguished MSA from PD,but in contrast to PD,no substantial astrocytic or microglialα-Syn accumulation in MSA occurred.These data confirm glial-specific changes between these diseases when immunolabelling the N-terminus epitope.In comparison,N-terminus neuronalα-Syn was present in PD and MSA,with most MSA neurons lacking pS129α-Syn proteoforms.This explains why characterisation of neuronal MSA pathologies is lacking and challenges the reliance on pS129 antibodies for the accurate quantification ofα-Syn pathological load acrossα-synucleinopathies.Conclusions These findings underscore the necessity of utilising a multiplex approach to detectα-Syn,most importantly including the N-terminus,to capture the entire spectrum ofα-Syn proteoforms inα-synucleinopathies.The data provide novel insights toward the biological differentiation of theseα-synucleinopathies and pave the way for more refined antemortem diagnostic methods to facilitate early identification and intervention of these neurodegenerative diseases.
