“…Thy1 has been implicated in nervous system development, neuronal injury, and immune response [ 37 ], and was found to be hypomethylated and downregulated in group 1 relative to group 2. Our results also show that mitogen-activated protein kinase 8 interacting protein 3 ( MAPK8IP3 ), recently implicated in nerve degeneration and axonal neuropathy [ 38 ], is hypomethylated and upregulated in group 1 compared to group 2. Fig.…”
Section: Resultssupporting
confidence: 71%
“…We also detected hypomethylated and upregulated MAPK8IP3, a scaffold protein for c-Jun N-terminal kinase (JNK), in sural nerves of patients with higher HbA1c. In addition to its emerging role in nerve degeneration and axonal neuropathy [38], MAPK8IP3 may be an important player in the progression of human DPN through its close interaction with Toll-like receptor 4 (TLR4) and JNKs [56]. We recently demonstrated a role for TLR4 in immune-mediated inflammation in murine DPN [57].…”
Background: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). Although the cellular and molecular mechanisms of DPN are poorly understood, we and others have shown that altered gene expression and DNA methylation are implicated in disease pathogenesis. However, how DNA methylation might functionally impact gene expression and contribute to nerve damage remains unclear. Here, we analyzed genome-wide transcriptomic and methylomic profiles of sural nerves from T2D patients with DPN. Results: Unbiased clustering of transcriptomics data separated samples into groups, which correlated with HbA1c levels. Accordingly, we found 998 differentially expressed genes (DEGs) and 929 differentially methylated genes (DMGs) between the groups with the highest and lowest HbA1c levels. Functional enrichment analysis revealed that DEGs and DMGs were enriched for pathways known to play a role in DPN, including those related to the immune system, extracellular matrix (ECM), and axon guidance. To understand the interaction between the transcriptome and methylome in DPN, we performed an integrated analysis of the overlapping genes between DEGs and DMGs. Integrated functional and network analysis identified genes and pathways modulating functions such as immune response, ECM regulation, and PI3K-Akt signaling. Conclusion: These results suggest for the first time that DNA methylation is a mechanism regulating gene expression in DPN. Overall, DPN patients with high HbA1c have distinct alterations in sural nerve DNA methylome and transcriptome, suggesting that optimal glycemic control in DPN patients is an important factor in maintaining epigenetic homeostasis and nerve function.
“…Thy1 has been implicated in nervous system development, neuronal injury, and immune response [ 37 ], and was found to be hypomethylated and downregulated in group 1 relative to group 2. Our results also show that mitogen-activated protein kinase 8 interacting protein 3 ( MAPK8IP3 ), recently implicated in nerve degeneration and axonal neuropathy [ 38 ], is hypomethylated and upregulated in group 1 compared to group 2. Fig.…”
Section: Resultssupporting
confidence: 71%
“…We also detected hypomethylated and upregulated MAPK8IP3, a scaffold protein for c-Jun N-terminal kinase (JNK), in sural nerves of patients with higher HbA1c. In addition to its emerging role in nerve degeneration and axonal neuropathy [38], MAPK8IP3 may be an important player in the progression of human DPN through its close interaction with Toll-like receptor 4 (TLR4) and JNKs [56]. We recently demonstrated a role for TLR4 in immune-mediated inflammation in murine DPN [57].…”
Background: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes (T2D). Although the cellular and molecular mechanisms of DPN are poorly understood, we and others have shown that altered gene expression and DNA methylation are implicated in disease pathogenesis. However, how DNA methylation might functionally impact gene expression and contribute to nerve damage remains unclear. Here, we analyzed genome-wide transcriptomic and methylomic profiles of sural nerves from T2D patients with DPN. Results: Unbiased clustering of transcriptomics data separated samples into groups, which correlated with HbA1c levels. Accordingly, we found 998 differentially expressed genes (DEGs) and 929 differentially methylated genes (DMGs) between the groups with the highest and lowest HbA1c levels. Functional enrichment analysis revealed that DEGs and DMGs were enriched for pathways known to play a role in DPN, including those related to the immune system, extracellular matrix (ECM), and axon guidance. To understand the interaction between the transcriptome and methylome in DPN, we performed an integrated analysis of the overlapping genes between DEGs and DMGs. Integrated functional and network analysis identified genes and pathways modulating functions such as immune response, ECM regulation, and PI3K-Akt signaling. Conclusion: These results suggest for the first time that DNA methylation is a mechanism regulating gene expression in DPN. Overall, DPN patients with high HbA1c have distinct alterations in sural nerve DNA methylome and transcriptome, suggesting that optimal glycemic control in DPN patients is an important factor in maintaining epigenetic homeostasis and nerve function.
“…Notably, mutations in the KIF5C kinesin gene have been reported in a number of patients with polymicrogyria or microcephaly, mutations in the KIF2A kinesin gene have been reported in a small group of patients with reduced cortical gyri (agyria/pachygyria) [54,61], and patients with mutations in the KIF1A kinesin gene have been found to develop pachygyria [62] and an unusual progressive form of microcephaly [63]. Noticeably, other kinesin families have been implicated in other neurodevelopmental pathologies [64–66].…”
Section: Microtubule Basics Dynamic Instability and Partnersmentioning
Malformations of cortical development (MCDs) are a group of severe brain malformations associated with intellectual disability and refractory childhood epilepsy. Human missense heterozygous mutations in the 9 α‐tubulin and 10 β‐tubulin isoforms forming the heterodimers that assemble into microtubules (MTs) were found to cause MCDs. However, how a single mutated residue in a given tubulin isoform can perturb the entire microtubule population in a neuronal cell remains a crucial question. Here, we examined 85 MCD‐associated tubulin mutations occurring in TUBA1A, TUBB2, and TUBB3 and their location in a three‐dimensional (3D) microtubule cylinder. Mutations hitting residues exposed on the outer microtubule surface are likely to alter microtubule association with partners, while alteration of intradimer contacts may impair dimer stability and straightness. Other types of mutations are predicted to alter interdimer and lateral contacts, which are responsible for microtubule cohesion, rigidity, and dynamics. MCD‐associated tubulin mutations surprisingly fall into all categories, thus providing unexpected insights into how a single mutation may impair microtubule function and elicit dominant effects in neurons.
“…Our results, which parallel and extend recent observations from rodent models, emphasize the power of human iPSC-derived neurons as a valuable tool for investigating human neuronal cell biology and neurodegenerative disease mechanisms. These new observations are also relevant for the development of models to study recently discovered neurodevelopmental defects arising from mutations in the human JIP3 (also known as MAPK8IP3 ) gene (Iwasawa et al ., 2019; Platzer et al ., 2019).…”
The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer's disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology.
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