Obesity‐associated type 2 diabetes and accompanying diseases have developed into a leading human health risk across industrialized and developing countries. The complex molecular underpinnings of how lipid overload and lipid metabolites lead to the deregulation of metabolic processes are incompletely understood. We assessed hepatic post‐translational alterations in response to treatment of cells with saturated and unsaturated free fatty acids and the consumption of a high‐fat diet by mice. These data revealed widespread tyrosine phosphorylation changes affecting a large number of enzymes involved in metabolic processes as well as canonical receptor‐mediated signal transduction networks. Targeting two of the most prominently affected molecular features in our data, SRC ‐family kinase activity and elevated reactive oxygen species, significantly abrogated the effects of saturated fat exposure in vitro and high‐fat diet in vivo . In summary, we present a comprehensive view of diet‐induced alterations of tyrosine signaling networks, including proteins involved in fundamental metabolic pathways.
Alzheimer's disease (AD) is a form of dementia characterized by amyloid-β plaques and Tau neurofibrillary tangles that progressively disrupt neural circuits in the brain. The signaling networks underlying the pathological changes in AD are poorly characterized at the level phosphoproteome. Using mass spectrometry, we performed a combined analysis of the tyrosine, serine, and threonine phosphoproteome, and proteome of temporal cortex tissue from AD patients and aged matched controls. We identified several co-correlated peptide modules that were associated with varying levels of phospho-Tau, oligodendrocyte, astrocyte, microglia, and neuronal pathologies in AD patients. We observed phosphorylation sites on kinases targeting Tau as well as other novel signaling factors that were correlated with these peptide modules. Finally, we used a data-driven statistical modeling approach to identify individual peptides and co-correlated signaling networks that were predictive of AD histopathologies. Together, these results build a map of pathology-associated phosphorylation signaling events occurring in AD.
Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia. The human paralog Siglec‐8 was also upregulated on microglia in AD. Siglec‐F and Siglec‐8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV‐2 cell line and human stem cell‐derived microglia models. Siglec‐F overexpression activates an endocytic and pyroptotic inflammatory response in BV‐2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine‐based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV‐2 cells. Collectively, our results point to an important role for mouse Siglec‐F and human Siglec‐8 in regulating microglial activation during neurodegeneration.
Alzheimer's disease (AD) is a form of dementia characterized by amyloid-β plaques and Tau neurofibrillary tangles that progressively disrupt neural circuits in the brain. The signaling networks underlying the pathological changes in AD are poorly characterized at the level phosphoproteome. Using mass spectrometry, we performed a combined analysis of the tyrosine, serine, and threonine phosphoproteome, and proteome of temporal cortex tissue from AD patients and aged matched controls. We identified several co-correlated peptide modules that were associated with varying levels of phospho-Tau, oligodendrocyte, astrocyte, microglia, and neuronal pathologies in AD patients. We observed phosphorylation sites on kinases targeting Tau as well as other novel signaling factors that were correlated with these peptide modules. Finally, we used a data-driven statistical modeling approach to identify individual peptides and co-correlated signaling networks that were predictive of AD histopathologies. Together, these results build a map of pathology-associated phosphorylation signaling events occurring in AD.
In neurodegenerative proteinopathies, intracellular inclusions are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. Patient- derived iPSC models, while promising for disease modeling, do not form analogous inclusions in a reasonable timeframe and suffer from limited tractability and scalability. Here, we developed an iPSC toolbox that utilizes piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of misfolding-prone proteins. The system is scalable and amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of- principle, cortical neuron alpha-synuclein inclusionopathy models were engineered to form inclusions spontaneously or through exogenous seeding by alpha-synuclein fibrils. These models recapitulated known fibril- and lipid-rich inclusion subtypes in human brain, shedding light on their formation and consequences. Genetic-modifier and protein-interaction screens identified sequestered proteins in these inclusions, including RhoA, that were deleterious to cells when lost. This new iPSC platform should facilitate biological and drug discovery for neurodegenerative proteinopathies.
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