Motoneuron programmed cell death in response to proBDNF

Taylor, Anna; Gifondorwa, David J.; Robinson, Mac; Strupe, Jane L.; Prevette, David; Johnson, James E.; Hempstead, Barbara L.; Oppenheim, Ronald W.; Milligan, Carolanne E.

doi:10.1002/dneu.20964

Cited by 41 publications

(27 citation statements)

References 92 publications

(137 reference statements)

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“…There has been evidence of BDNF being produced in smooth and skeletal muscle (65, 66), but no studies have specifically examined the effects of proBDNF on muscle. However, several studies discuss the role of proBDNF in cell death and atrophy of motoneurons (63, 67). Here we found that higher proBDNF only in L1CAM+ EVs is associated with walking speed decline, suggesting that proBDNF plays a role in motor function and aging-associated motor decline.…”

Section: Discussionmentioning

confidence: 99%

Walking speed decline in older adults is associated with elevated pro-BDNF in plasma extracellular vesicles

Suire

Eitan

Shaffer

et al. 2017

Experimental Gerontology

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Background Brain-derived neurotrophic factor (BDNF) is produced by cleavage of proBDNF, and BDNF and proBDNF may play antagonistic roles in nervous system development, learning, memory and neuronal stress resistance. BDNF and proBDNF are present in blood, but the origin and relative contributions of soluble and extracellular vesicle (EV)-associated levels are unknown. Methods In this study we used validated immunoassays to measure proBDNF and BDNF levels in plasma, total plasma EVs and a subpopulation of EVs enriched for neuronal origin (expressing the neuronal marker L1CAM) in 150 Baltimore Longitudinal Study of Aging participants with and without decline in walking speed (reflecting aging-associated motor decline). Results Levels of BDNF and proBDNF were highest in L1CAM+ EVs. Participants with walking speed decline had higher levels of proBDNF in L1CAM+ EVs compared to non-decliners, but no differences in proBDNF levels in plasma and total EV. Conclusions Our findings suggest that levels of proBDNF and BDNF in circulating L1CAM+ EVs might be used as biomarkers for conditions involving altered BDNF signaling.

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Section: Discussionmentioning

confidence: 99%

Walking speed decline in older adults is associated with elevated pro-BDNF in plasma extracellular vesicles

Suire

Eitan

Shaffer

et al. 2017

Experimental Gerontology

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“…As MNs are the only neurons that project axons out of the CNS to innervate targets, their survival is controlled by target-derived trophic factors (Hamburger, 1992;Oppenheim, 1989;Taylor et al, 2012). In addition, GDNF and proprioceptive afferent neurons impinging on MNs also contribute to the survival surveillance of MNs (Kanning et al, 2010).…”

Section: Mir-17$92 Exhibits Intrinsic and Cell-autonomous Functions Imentioning

confidence: 99%

Mir-17∼92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN

Tung

Peng

et al. 2015

Cell Reports

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Motor neurons (MNs) are unique because they project their axons outside of the CNS to innervate the peripheral muscles. Limb-innervating lateral motor column MNs (LMC-MNs) travel substantially to innervate distal limb mesenchyme. How LMC-MNs fine-tune the balance between survival and apoptosis while wiring the sensorimotor circuit en route remains unclear. Here, we show that the mir-17∼92 cluster is enriched in embryonic stem cell (ESC)-derived LMC-MNs and that conditional mir-17∼92 deletion in MNs results in the death of LMC-MNs in vitro and in vivo. mir-17∼92 overexpression rescues MNs from apoptosis, which occurs spontaneously during embryonic development. PTEN is a primary target of mir-17∼92 responsible for LMC-MN degeneration. Additionally, mir-17∼92 directly targets components of E3 ubiquitin ligases, affecting PTEN subcellular localization through monoubiquitination. This miRNA-mediated regulation modulates both target expression and target subcellular localization, providing LMC-MNs with an intricate defensive mechanism that controls their survival.

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“…Since then, there have been few studies examining the role of p75 retrograde apoptotic signaling during normal development. Taylor et al [29] provided evidence of p75-mediated apoptosis during development of motor neurons in the chick embryo. They demonstrated that muscle cells release pro-BDNF, which induced apoptosis of spinal motor neurons in culture, and the developmental apoptosis of these neurons in vivo was prevented by antibodies blocking p75; Sortilin (a Vps10p co-receptor) or pro-BDNF.…”

Section: Retrograde Apoptotic Signaling By the P75 Receptormentioning

confidence: 99%

Retrograde apoptotic signaling by the p75 neurotrophin receptor

Pathak

Carter

2017

Neuronal Signaling

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Neurotrophins are target-derived factors necessary for mammalian nervous system development and maintenance. They are typically produced by neuronal target tissues and interact with their receptors at axonal endings. Therefore, locally generated neurotrophin signals must be conveyed from the axon back to the cell soma. Retrograde survival signaling by neurotrophin binding to Trk receptors has been extensively studied. However, neurotrophins also bind to the p75 receptor, which can induce apoptosis in a variety of contexts. Selective activation of p75 at distal axon ends has been shown to generate a retrograde apoptotic signal, although the mechanisms involved are poorly understood. The present review summarizes the available evidence for retrograde proapoptotic signaling in general and the role of the p75 receptor in particular, with discussion of unanswered questions in the field. In-depth knowledge of the mechanisms of retrograde apoptotic signaling is essential for understanding the etiology of neurodegeneration in many diseases and injuries.

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Motoneuron programmed cell death in response to proBDNF

Cited by 41 publications

References 92 publications

Walking speed decline in older adults is associated with elevated pro-BDNF in plasma extracellular vesicles

Walking speed decline in older adults is associated with elevated pro-BDNF in plasma extracellular vesicles

Mir-17∼92 Governs Motor Neuron Subtype Survival by Mediating Nuclear PTEN

Retrograde apoptotic signaling by the p75 neurotrophin receptor

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