Establishing Myelinating Cocultures Using Human iPSC-Derived Sensory Neurons to Investigate Axonal Degeneration and Demyelination

2020 ◽  
pp. 111-129
Author(s):  
Alex J. Clark
Keyword(s):  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Human Ipsc

scholarly journals BPAG1n4 is essential for retrograde axonal transport in sensory neurons

2003 ◽  
Vol 163 (2) ◽  
pp. 223-229 ◽  
Author(s):  
Jia-Jia Liu ◽  
Jianqing Ding ◽  
Anthony S. Kowal ◽  
Timothy Nardine ◽  
Elizabeth Allen ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Retrograde Axonal Transport ◽  
Binding Assays ◽  
Yeast Two Hybrid ◽  
Cytoskeletal Networks ◽  
Two Hybrid ◽  
Hybrid Screening

Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.

Pain responses of cultured human iPSC-derived sensory neurons using high-throughput MEA system

2018 ◽  
Vol 93 ◽  
pp. 166 ◽  
Author(s):  
Aoi Odawara ◽  
Naoki Matsuda ◽  
Yuto Ishibashi ◽  
Ikuro Suzuki
Keyword(s):  
Sensory Neurons ◽  
High Throughput ◽  
Human Ipsc ◽  
Pain Responses

Axonal degeneration of ascending sensory neurons in gracile axonal dystrophy mutant mouse

1990 ◽  
Vol 80 (2) ◽  
pp. 145-151 ◽  
Author(s):  
T. Kikuchi ◽  
M. Mukoyama ◽  
K. Yamazaki ◽  
H. Moriya
Keyword(s):  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Mutant Mouse ◽  
Axonal Dystrophy ◽  
Gracile Axonal Dystrophy

scholarly journals Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy

2021 ◽  
Vol 118 (4) ◽  
pp. e2012685118
Author(s):  
Maria Elena Pero ◽  
Cristina Meregalli ◽  
Xiaoyi Qu ◽  
Grace Ji-eun Shin ◽  
Atul Kumar ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Pathogenic Role ◽  
Unmyelinated Fibers ◽  
Microtubule Stability ◽  
Altered Regulation

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

scholarly journals Pathogenic Role of Delta 2 Tubulin in Bortezomib Induced Peripheral Neuropathy

2019 ◽  
Author(s):  
Maria Elena Pero ◽  
Cristina Meregalli ◽  
Xiaoyi Qu ◽  
Atul Kumar ◽  
Matthew Shorey ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Axonal Degeneration ◽  
Pathogenic Role ◽  
Pathogenic Mechanisms ◽  
Mitochondria Dynamics

ABSTRACTThe pathogenesis of chemotherapy induced peripheral neuropathy (CIPN) is still poorly understood. Herein, we found that the CIPN-causing drug, bortezomib (Bort), induces delta 2 tubulin (D2) while affecting MT stability and dynamics in sensory neurons, and that accumulation of D2 is a hallmark of Bort-induced peripheral neuropathy in humans. Furthermore, while induction of D2 was sufficient to cause axonopathy and inhibit mitochondria motility, reducing D2 alleviated both axonal degeneration and loss of mitochondria motility promoted by Bort. Altogether, our data demonstrate that Bort, structurally unrelated to tubulin poisons, can affect the tubulin cytoskeleton in sensory neurons in vitro, in vivo and in humans, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. They further reveal a previously unrecognized pathogenic role for D2 in bortezomib-causing CIPN through its regulation of mitochondria dynamics.

The Complex Clinical and Genetic Landscape of Hereditary Peripheral Neuropathy

2021 ◽  
Vol 16 (1) ◽  
pp. 487-509
Author(s):  
Soumitra Ghosh ◽  
Warren G. Tourtellotte
Keyword(s):  
Peripheral Neuropathy ◽  
Sensory Neurons ◽  
Neurological Disorders ◽  
Axonal Degeneration ◽  
Early Age ◽  
Single Mutation ◽  
Disease Phenotype ◽  
Genetic Landscape ◽  
Hereditary Peripheral Neuropathy ◽  
Generation Sequencing

Hereditary peripheral neuropathy (HPN) is a complex group of neurological disorders caused by mutations in genes expressed by neurons and Schwann cells. The inheritance of a single mutation or multiple mutations in several genes leads to disease phenotype. Patients exhibit symptoms during development, at an early age or later in adulthood. Most of the mechanistic understanding about these neuropathies comes from animal models and histopathological analyses of postmortem human tissues. Diagnosis is often very complex due to the heterogeneity and overlap in symptoms and the frequent overlap between various genes and different mutations they possess. Some symptoms in HPN are common through different subtypes such as axonal degeneration, demyelination, and loss of motor and sensory neurons, leading to similar physiologic abnormalities. Recent advances in gene-targeted therapies, genetic engineering, and next-generation sequencing have augmented our understanding of the underlying pathogenetic mechanisms of HPN.

scholarly journals Anthrax Toxin as a Molecular Platform to Target Nociceptive Neurons and Modulate Pain

2020 ◽  
Author(s):  
Nicole J. Yang ◽  
Jörg Isensee ◽  
Dylan Neel ◽  
Sai Man Liu ◽  
Han Xiong Bear Zhang ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Anthrax Toxin ◽  
Bacterial Toxin ◽  
Nociceptive Neurons ◽  
Analgesic Effects ◽  
Selective Targeting ◽  
Anthrax Toxins ◽  
And Function ◽  
Human Ipsc

ABSTRACTBacterial toxins are able to act on neurons to modulate signaling and function. Here, we find that nociceptive sensory neurons that mediate pain are enriched in the receptor for anthrax toxins, ANTXR2. Anthrax Edema Toxin (ET) induced cAMP and PKA signaling in Nav1.8+ nociceptive neurons and modulated pain in vivo. Peripherally administered ET mediated mechanical allodynia in naïve mice and during B. anthracis infection. Intrathecally administered ET produced analgesic effects, potently blocking pain-like behaviors in multiple mouse models of inflammatory and chronic neuropathic pain. Nociceptor-specific ablation of ANTXR2 attenuated ET-induced signaling and analgesia. Modified anthrax toxin successfully delivered exogenous protein cargo into nociceptive neurons, illustrating utility of the anthrax toxin system as a molecular platform to target pain. ET further induced signaling in human iPSC-derived sensory neurons. Our findings highlight novel interactions between a bacterial toxin and nociceptors that may be utilized for developing new pain therapeutics.SUMMARYANTXR2 expression on nociceptive neurons allows selective targeting and modulation of pain by native and engineered anthrax toxins.

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