Molecular mechanisms of Tau and TDP-43 pathology, and interaction of co-pathology in neurodegenerative disease

Neurodegeneration research has increasingly recognized the pivotal contributions of specific proteinopathies to cognitive decline and behavioral alterations seen with aging. Among these, transactive response DNA-binding protein 43 (TDP-43) and tau have emerged as central players in conditions such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. While tauopathies and TDP-43 proteinopathies were initially considered largely distinct, growing evidence reveals overlapping distribution patterns, synergistic interactions, and converging mechanisms underlying their accumulation in vulnerable neuronal populations. This complexity has sparked debate regarding their relative contributions to neurodegenerative phenotypes, the sequence of their pathological events, and the reasons for their frequent comorbidity, especially in older individuals.Recent studies employing neuropathological, genetic, and model-based approaches have shed new light on the molecular crosstalk between TDP-43 and tau. There is increasing evidence that their co-occurrence exacerbates neuronal dysfunction and accelerates cognitive decline beyond what is seen in single pathology cases. Advances in imaging, biomarker development, and human postmortem analyses also continue to refine our ability to detect these proteins in vivo and assess their independent and interactive effects. Nonetheless, the precise biological mechanisms by which TDP-43 and tau drive neurodegeneration, individually and together, remain poorly defined, as do the clinical consequences of their overlap in diverse neurocognitive syndromes.This Research Topic aims to deepen our understanding of the roles and interplay of TDP-43 and tau in the pathogenesis of neurodegenerative diseases, especially in the context of cognitive aging and behavioral deterioration. We seek to clarify outstanding questions regarding the causality, sequence, and mechanisms of TDP-43 and tau pathology, unravel their shared and distinct impacts on brain networks, and explore how their interaction shapes disease progression and outcomes. Insights generated may inform diagnostic, prognostic, and therapeutic innovations tailored to patients with complex proteinopathies.We particularly encourage submissions that employ sensitive, multidimensional approaches to cognitive assessment beyond screening measures such as MMSE and MoCA, as these allow for a more precise understanding of cognitive and behavioral consequences of tau and TDP-43 pathology.To gather further insights into the intersection of TDP-43 and tau pathologies in aging and behavior, we welcome articles addressing, but not limited to, the following themes:o Molecular and cellular mechanisms of TDP-43 and tau aggregation and toxicityo Pathological and clinical correlates of TDP-43 and tau co-pathology in neurodegenerative diseaseso Experimental models exploring TDP-43, tau, and their interactionso Biomarker development for early detection and differentiation of TDP-43/tau associated disorderso Behavioral and cognitive impacts of single versus multiple proteinopathies in agingo Genetic, environmental, and lifestyle risk modifiers in TDP-43 and tau pathologyo Therapeutic strategies targeting TDP-43 and/or tau for neuroprotection and disease modificationWe invite the submission of original research articles, reviews, mini-reviews, and methodological reports within the scope of this Research Topic. Topic editors: Meghraj Singh Baghel, Aswathy Peethambaran Mallika, Deepak Chhangani Source: https://www.frontiersin.org/research-topics/78787/molecular-mechanisms-of-tau-and-tdp-43-pathology-and-interaction-of-co-pathology-in-neurodegenerative-disease