A neuron autonomous role for the familial dysautonomia gene<i>ELP1</i>in sympathetic and sensory target tissue innervation

Jackson, Marisa Z.; Gruner, Katherine; Qin, Charles; Tourtellotte, Warren G.

doi:10.1242/dev.107797

Cited by 73 publications

(128 citation statements)

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“…It has been postulated that neurons die in FD because of an inability to innervate correctly their targets from which they receive essential survival stimuli in the form of neurotrophins (36,37). We show here that incubation in NGF is insufficient to rescue the small-diameter TrkA + , Ikbkap −/− neurons.…”

Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 64%

“…FD patients have impaired blood pressure regulation and suffer from sudden death resulting from cardiac arrhythmias and asystole (44). These symptoms coincide with a decrease in sympathetic innervation of the heart, particularly its ventral apex (37,45). Based on our finding that BGP-15 could rectify actin dynamics in Ikbkap −/− neurons in vitro, we asked whether treatment with the compound could reverse the defect in cardiac innervation that has previously been reported in Ikbkap −/− embryos (37).…”

Section: Bgp-15 Improves Ikbkapmentioning

confidence: 99%

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BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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Section: Bgp-15 Normalizes Impaired Actin Dynamics In Ikbkapmentioning

confidence: 64%

Section: Bgp-15 Improves Ikbkapmentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, we found that FS þ Elp1-TcKO neurons had comparable survival to Elp1-TCtl neurons when 10 ng/mL NGF was present in both CB and DA compartments ( Figure 2C), consistent with our previously published results that used dissociated Elp1-deficient neurons that were completely immersed in NGF. 98 By contrast, when NGF was restricted to distal axons in the DA compartment only 22% of FS þ Elp1-TcKO neurons survived. Elp1-TcKO neurons with 10 ng/mL in the DA compartment survived similar to Elp1-TCtl neurons with 1 ng/mL in the DA compartment; a 10-fold decreased sensitivity in their signaling response to target-derived NGF.…”

Section: Fd: a Model Of Abnormal Retrograde Ngf Signaling Resulting Imentioning

confidence: 99%

“…Thus, sympathetic dysautonomia in FD is likely explained by impairment in retrograde NGF signaling which leads to survival and target tissue innervation abnormalities in the context of limited NGF produced by target tissues. 98 How does Elp1 function in retrograde NGF signaling? Little is currently known about how Elp1 functions in axons, but its role as a component of the transcriptional elongator complex within the nucleus may provide some clues.…”

Section: Fd: a Model Of Abnormal Retrograde Ngf Signaling Resulting Imentioning

confidence: 99%

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Axon Transport and Neuropathy

Tourtellotte

2016

The American Journal of Pathology

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Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. (Am J Pathol 2016, 186: 489e499; http://dx

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