TL;DR
A transcriptional framework linking early TDP-43 stress responses to pathological aggregation in AD is provided, and potential upstream therapeutic targets are revealed, including ERK1/2, PI3K, small GTPases, and mRNA splicing pathways.
Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.
While predominantly nuclear localized in healthy cells, TDP-43 can transit between the nucleus and cytoplasm. In frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS), TDP-43 accumulates in hyperphosphorylated cytoplasmic aggregates. However, a subset of patients develops nuclear aggregates. Expression of wild-type TDP-43 in C. elegans neurons results in nuclear protein accumulation and toxic gain of function. To enable comparative study of nuclear and cytoplasmic TDP-43 phenotypes, we generated new models with inactivating mutations in the nuclear localization sequence (NLS) of TDP-43. When compared to nuclear TDP-43 strains, similar protein levels of cytoplasmic TDP-43 cause less neuronal dysfunction in C. elegans . Using RNA sequencing, we determine that transcriptomes are largely unchanged in these models. However, we identify innate immune pathway increases in response to cytoplasmic but not nuclear TDP-43. We find phosphorylation-mediated neurotoxicity of both cytoplasmic and nuclear localized TDP-43 is controlled by the phosphatase calcineurin. We also find that overexpression of the unfolded protein response (UPR) transcription factor XBP-1s worsens outcomes for wild-type TDP-43 animals but improves TDP-43 ΔNLS, suggesting different pathways controlling toxicity and clearance of nuclear versus cytoplasmic TDP-43. Taken together, these data support shared and distinct cellular responses to nuclear versus cytoplasmic TDP-43 localization in an intact animal nervous system. This comparative approach supports a better understanding of human disease and informs therapeutic development for pathological subtypes of TDP-43 proteinopathies.
Current evidence on the RNA regulatory networks in PD is examined, highlighting the role of transcript isoforms and RBPs in neuronal dysfunction and emerging data suggest that dysregulation of RNA binding proteins (RBPs) may influence RNA processing in PD.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, protein aggregation, and widespread molecular alterations in the brain. In this study, we applied quantitative mass spectrometry-based proteomics and phosphoproteomics to characterize synaptosomes and sarkosyl-insoluble protein inclusions from the post-mortem frontal lobes of AD and control cases. We identified >3700 proteins across both fractions, revealing AD-associated changes in synaptic composition and phosphorylation patterns. Proteomic analyses indicated mitochondrial deficits and disruptions in vesicle trafficking within synapses, whereas insoluble protein inclusions showed an accumulation of spliceosomal components and glial activation markers as well as an enrichment of N-terminally truncated amyloid beta peptides in AD cases, suggesting involvement of postfibrillar processing events mediated by specific proteases in amyloid plaque pathology. Phosphoproteomic analysis revealed extensive alterations in pathways regulating vesicle trafficking, Golgi homeostasis, and synaptic function. We observed increased tau phosphorylation at AD-associated sites in insoluble inclusions and distinct phosphorylation changes in synaptic tau, particularly at S285 and S305, suggesting altered tau function and aggregation properties. These findings provide new molecular insights into AD-related nerve terminal composition and protein aggregation, advancing our understanding of disease-associated changes at the subcellular level.