Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury

Broggini, Thomas; Schnell, Lisa; Ghoochani, Ali; Mateos, José Marı́a; Buchfelder, Michael; Wiendieck, Kurt; Schäfer, Michael K. E.; Eyüpoglu, Ilker Y.; Savaskan, Nicolai Ε.

doi:10.18632/aging.101066

Cited by 17 publications

(54 citation statements)

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“…Studies in mice have shown that after neuronal injury, overexpression of LPPR1 enhances axonal growth, improves motor behavior, and promotes functional recovery. 33 , 34 Extrapolating to our findings, we propose that LPPR1 is involved, not necessarily in the cause of PD, rather in response to damage, and influences the efficacy of regeneration and the subsequent rate of deterioration in preclinical PD. The actual cause of injury and neuronal death is not stipulated in this hypothesis; it could be head trauma, environmental toxins or genetic, but once the initial damage is incurred, it is the efficacy of intrinsic mechanisms of repair that determine the rate of disease progression.…”

Section: Discussionsupporting

confidence: 75%

“…PAGE I participants being significantly older than NGRC and PAGE P participants may also be a factor. LPPR1 promotes neuroregeneration, 32 – 34 but its expression diminishes with age to nearly undetectable level by age 40 years ( figure 2C ). One can speculate that some detrimental variants may not have an effect after a certain age when the gene is no longer expressed.…”

Section: Discussionmentioning

confidence: 99%

“…LPPR1 is one of the 5 members of a brain-specific gene family that modulates neuronal plasticity during development, aging, and after brain injury. 32 – 34 LPPR1 is the strongest driver of axonal outgrowth in the gene family. Studies in mice have shown that after neuronal injury, overexpression of LPPR1 enhances axonal growth, improves motor behavior, and promotes functional recovery.…”

Section: Discussionmentioning

confidence: 99%

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Plasticity-related gene 3 ( LPPR1 ) and age at diagnosis of Parkinson disease

et al. 2018

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ObjectiveTo identify modifiers of age at diagnosis of Parkinson disease (PD).MethodsGenome-wide association study (GWAS) included 1,950 individuals with PD from the NeuroGenetics Research Consortium (NGRC) study. Replication was conducted in the Parkinson's, Genes and Environment study, including 209 prevalent (PAGEP) and 517 incident (PAGEI) PD cases. Cox regression was used to test association with age at diagnosis. Individuals without neurologic disease were used to rule out confounding. Gene-level analysis and functional annotation were conducted using Functional Mapping and Annotation of GWAS platform (FUMA).ResultsThe GWAS revealed 2 linked but seemingly independent association signals that mapped to LPPR1 on chromosome 9. LPPR1 was significant in gene-based analysis (p = 1E-8). The top signal (rs17763929, hazard ratio [HR] = 1.88, p = 5E-8) replicated in PAGEP (HR = 1.87, p = 0.01) but not in PAGEI. The second signal (rs73656147) was robust with no evidence of heterogeneity (HR = 1.95, p = 3E-6 in NGRC; HR = 2.14, p = 1E-3 in PAGEP + PAGEI, and HR = 2.00, p = 9E-9 in meta-analysis of NGRC + PAGEP + PAGEI). The associations were with age at diagnosis, not confounded by age in patients or in the general population. The PD-associated regions included variants with Combined Annotation Dependent Depletion (CADD) scores = 10–19 (top 1%–10% most deleterious mutations in the genome), a missense with predicted destabilizing effect on LPPR1, an expression quantitative trait locus (eQTL) for GRIN3A (false discovery rate [FDR] = 4E-4), and variants that overlap with enhancers in LPPR1 and interact with promoters of LPPR1 and 9 other brain-expressed genes (Hi-C FDR < 1E-6).ConclusionsThrough association with age at diagnosis, we uncovered LPPR1 as a modifier gene for PD. LPPR1 expression promotes neuronal regeneration after injury in animal models. Present data provide a strong foundation for mechanistic studies to test LPPR1 as a driver of response to damage and a therapeutic target for enhancing neuroregeneration and slowing disease progression.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Plasticity-related gene 3 ( LPPR1 ) and age at diagnosis of Parkinson disease

et al. 2018

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“…40 In brief, following 20 min incubation on ice, samples were centrifuged at 8000 r.p.m for 10 min. Supernatants were isolated and protein concentration measured with the NanoVue Plus Spectrophotometer (GE Healthcare, UK).…”

Section: Methodsmentioning

confidence: 99%

ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner

et al. 2017

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Activating transcription factor 4 (ATF4) is a critical mediator of metabolic and oxidative homeostasis and cell survival. ATF4 is elevated in response to diverse microenvironmental stresses, including starvation, ER stress damages and exposure to toxic factors. Here we show that ATF4 expression fosters the malignancy of primary brain tumors (WHO grade III and IV gliomas) and increases proliferation and tumor angiogenesis. Hence, ATF4 expression promotes cell migration and anchorage-independent cell growth, whereas siRNA-mediated knockdown of ATF4 attenuates these features of malignancy in human gliomas. Further experiments revealed that ATF4-dependent tumor promoting effects are mediated by transcriptional targeting the glutamate antiporter xCT/SCL7A11 (also known as system Xc-). Thus, xCT is elevated as a consequence of ATF4 activation. We further found evidence that ATF4-induced proliferation can be attenuated by pharmacological or genetic xCT inhibition and ferroptosis inducers such as sorafenib, erastin and GPx4 inhibitor RSL3. Further, fostered xCT expression promotes cell survival and growth in ATF4 knockdown cells. Moreover, increased xCT levels ameliorate sorafenib and erastin-induced ferroptosis. Conversely, ATF4 knockdown renders cells susceptible for erastin, sorafenib and RSL3-induced ferroptosis. We further identified that ATF4 promotes tumor-mediated neuronal cell death which can be alleviated by xCT inhibition. Moreover, elevated ATF4 expression in gliomas promotes tumor angiogenesis. Noteworthy, ATF4-induced angiogenesis could be diminished by ferroptosis inducers erastin and by GPx4 inhibitor RSL3. Our data provide proof-of-principle evidence that ATF4 fosters proliferation and induces a toxic microenvironmental niche. Furthermore, ATF4 increases tumor angiogenesis and shapes the vascular architecture in a xCT-dependent manner. Thus, inhibition of ATF4 is a valid target for diminishing tumor growth and vasculature via sensitizing tumor cells for ferroptosis.

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“…Another study in a model of incomplete SCI reported that neurotrophic upregulation demonstrated an injury-specific BDNF response including regenerative sprouting and increased connectivity of injured neurons with propriospinal interneurons [ 6 ]. Other promising targets include the PRG3 gene, which induces filopodia formation and axonal growth and has also been shown to overcome a range of neurite growth inhibitors, though not yet evaluated in SCI specifically [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury

Wang

Zhai

et al. 2017

Neural Plasticity

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DPSN axons mediate and maintain a variety of normal spinal functions. Unsurprisingly, DPSN tracts have been shown to mediate functional recovery following SCI. KLF7 could contribute to CST axon plasticity after spinal cord injury. In the present study, we assessed whether KLF7 could effectively promote DPSN axon regeneration and synapse formation following SCI. An AAV-KLF7 construct was used to overexpress KLF7. In vitro, KLF7 and target proteins were successfully elevated and axonal outgrowth was enhanced. In vivo, young adult C57BL/6 mice received a T10 contusion followed by an AAV-KLF7 injection at the T7–9 levels above the lesion. Five weeks later, overexpression of KLF7 was expressed in DPSN. KLF7 and KLF7 target genes (NGF, TrkA, GAP43, and P0) were detectably increased in the injured spinal cord. Myelin sparring at the lesion site, DPSN axonal regeneration and synapse formation, muscle weight, motor endplate morphology, and functional parameters were all additionally improved by KLF7 treatment. Our findings suggest that KLF7 promotes DPSN axonal plasticity and the formation of synapses with motor neurons at the caudal spinal cord, leading to improved functional recovery and further supporting the potential of AAV-KLF7 as a therapeutic agent for spinal cord injury.

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Plasticity Related Gene 3 (PRG3) overcomes myelin-associated growth inhibition and promotes functional recovery after spinal cord injury

Cited by 17 publications

References 56 publications

Plasticity-related gene 3 ( LPPR1 ) and age at diagnosis of Parkinson disease

Plasticity-related gene 3 ( LPPR1 ) and age at diagnosis of Parkinson disease

ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner

AAV-KLF7 Promotes Descending Propriospinal Neuron Axonal Plasticity after Spinal Cord Injury

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