Neurodegenerative diseases (NDDs) exhibit considerable molecular heterogeneity, making it difficult to pinpoint robust, disease-specific biomarkers. Although proteomic studies have deepened our understanding of individual disorders, systematic cross-disease comparisons with cross-platform validation remain scarce, especially for rare conditions like spinal and bulbar muscular atrophy (SBMA). To address this gap, we conducted a comparative plasma proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 264 participants across major neurodegenerative and related diagnostic groups, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), SBMA, and cognitively healthy controls. This unified framework allowed us to capture both disease-specific and shared protein signatures across neurodegenerative conditions. Candidate proteins were then validated in the UK Biobank (Olink Explore) and the Global Neurodegeneration Proteomics Consortium (SomaScan). Of 23 proteins assessed in the UK Biobank, four unique proteins (yielding six disease-protein associations) showed nominally significant and directionally concordant changes; of 20 proteins represented by 27 probes tested in the Global Neurodegeneration Proteomics Consortium, seven proteins reached nominal significance, all with full directional concordance across both cohorts. Notably, IGFBP2 was consistently elevated in AD and PD across independent datasets, pointing to shared metabolic dysregulation, while ADIPOQ showed parallel increases in the same conditions, reinforcing convergent shifts in energy metabolism. By contrast, CRTAC1 and COMP were selectively reduced in motor neuron diseases, suggesting disease-enriched alterations in extracellular matrix composition. Taken together, our findings provide a cross-disease, cross-platform framework for uncovering reproducible proteomic biomarkers and shed light on both overlapping and distinct molecular pathways in neurodegeneration.
Y. Choi, Shinrye Lee, Janbolat Ashim et al.· Acta Neuropathologica Commun...· 0 citations
Proper nervous system development is critical for brain function, and deficits in neural development are implicated in many brain disorders. Neurons are distinctly polarized cells where mRNA can be transported to distal structures like axons and dendrites. Recent discoveries of widespread mRNA chemical modifications raise the question of their post-transcriptional regulatory role in brain development and function. N6-methyladenosine (m6A), installed by the METTL3/METTL14 methyltransferase complex, is the most prevalent internal mRNA modification, influencing stability, translation, splicing, and localization. However, the impact of m6A modification on RNA transport in developing neurons is not well understood. In this study, we find that the ablation of Mettl14 in postmitotic neurons leads to impaired axonal projection during corticogenesis. RNA-seq and single-molecule in situ hybridization reveal mislocalization of mRNAs in neurites of neurons with m6A loss-of-function. Furthermore, m6A-SAC-seq to identify a single nucleotide resolution m6A maps in the perinatal brain uncovers m6A-tagged transcripts associated with synapse organization, mRNA processing, and axonogenesis. We also identify YTHDF2 as the reader protein responsible for mRNA transport in callosal projection axons. YTHDF2 interacts with motor proteins, translational regulators, and microtubules to facilitate distal transport of m6A-tagged mRNA. Our data suggest that FMRP may serve as a context-guiding interactor that reshapes the YTHDF2 complex by recruiting specific cofactors and motor proteins, thereby promoting transport rather than degradation of m⁶A-tagged transcripts. Together, these findings provide insight into the epitranscriptomic mechanisms governing axon projection and guidance during mammalian cortical neurogenesis. Precise mRNA transport into neurites is essential for neural circuit formation. Here, the authors show that m6A RNA marks recruit YTHDF2-associated transport machinery that favors transport over degradation, localizing selected mRNAs to neurites to promote cortical axon projection.
Bonsang Koo, Ajeet Kumar, H. Hwang et al.· Nature Communications· 0 citations
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