Neuroinflammatory signals drive Scoliosis in Zebrafish model

[Dingo]

Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis.

December 12, 2018

The etiopathogenesis of idiopathic scoliosis (IS), a highly prevalent spinal deformity that occurs in the absence of obvious congenital or physiological abnormalities, is poorly understood. Although recent zebrafish genetic studies have linked cilia motility and cerebrospinal fluid (CSF) flow defects with scoliosis progression, underlying mechanisms were not identified. Here, we use next-generation sequencing and conditional genetic methodologies to define the spatial and biological origins of spinal curve formation in ptk7 mutant zebrafish, a faithful IS model. We demonstrate that focal activation of proinflammatory signals within the spinal cord is associated with, and sufficient for, induction of spinal curvatures. Furthermore, administration of acetylsalicylic acid (aspirin) or N-acetylcysteine (NAC) to juvenile ptk7 mutants significantly reduces the incidence and/or severity of scoliosis phenotypes. Together, our results implicate neuroinflammation, downstream of CSF defects, in spinal curve formation and provide intriguing evidence that simple immunomodulating therapies might prove effective in managing idiopathic-like spinal deformities.

As is so often the case among common diseases inflammation may be the root cause of scoliosis. That appears to be the case in the Zebrafish model that researchers use to study IS.

Long story short: Eat your vegetables and don't eat processed food garbage. Hopefully ever. Modern, sugary food is highly inflammatory. Google for confirmation on diet and inflammation.

[Dingo]

Full study here: Neuroinflammatory signals drive spinal curve formation in zebrafish models of idiopathic scoliosis

Although a definitive link between neuroinflammation and human IS requires further study, inflammatory origins of scoliosis are not inconsistent with human clinical and genetic studies. Hyper-IgE (immunoglobulin E) syndrome, characterized by frequent bacterial infection and inflammation, has been associated with developmental scoliosis (31). Similarly, more than 50% of patients characterized by recurring nontuberculosis mycobacterial infection present with idiopathic-like spinal curvatures (32). To date, the biological consequences of most IS-associated variants identified in genetic and genome-wide association studies remain uncertain (1). For example, IS-associated variants linked to GPR126 have been functionally interrogated largely in the context of musculoskeletal origins of scoliosis (4, 33). However, because myelination requires GPR126 (34), regional demyelinating events downstream of GPR126 dysfunction could activate microglial inflammatory signals that initiate IS-like spinal curvature. Novel neuroinflammatory origins of IS identified in this study thus warrant a reexamination and interpretation of human IS clinical and genetic data.

Strikingly, we have demonstrated that treatment with common NSAIDs can have a significant and positive impact on the incidence and severity of scoliosis in our ptk7 mutant models. Notably, prophylactic treatment with NAC reduced the incidence of scoliosis in experimental cohorts by 79%. Furthermore, administration of NAC after scoliosis onset significantly reduced the severity of spinal curve progression. NAC is considered a well-tolerated and safe medication, with emerging clinical use for treating neurological and neurodevelopmental disorders in both children and adults [reviewed in (23, 35)]. The therapeutic potential of NAC in treating IS remains to be determined. However, given that simple immunomodulating therapies prove effective in managing zebrafish idiopathic-like spinal deformities, conservation of the mechanism could have profound impacts on the future prevention and treatment of human scoliosis.

[Dingo]

Sure enough the researchers were correct.

Hyper-IgE syndrome update

AD-HIES is characterized by eczematoid rashes, skin abscesses, recurrent sinopulmonary infections, mucocutaneous candidiasis, and malignancies.

Clinical features of hyper-IgE syndrome
Nonimmunologic frequency
Scoliosis 63%

Pulmonary Nontuberculous Mycobacterial Disease

Conclusions: Patients with PNTM infection are taller and leaner than control subjects, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis transmembrane conductance regulator mutations, but without recognized immune defects.

[Dingo]

I did a few minutes of digging and once again spinal deformity is associated with infections besides Polio.

Vertebral Osteomyelitis: Rare Spinal Infection Can Cause Severe Back Pain

Surgery may be considered if: You develop spinal deformity (such as scoliosis or kyphosis), or the deformity worsens.

The Zebrafish study was on the mark. Inflammation in the spine does cause deformity. It's well known.

[Pooka1]

Previous year this study was posted on the research part of this forum: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291318/ After reading it, I was curious enough to try the NAC that was referred to in the article. Long story short, my "idiopathic" scoliosis turned out to be a kind of miscommunication between cerebrospinal fluid and sensory nerve system. Some sensory nerves that were supposed to support my back didn't do so. After this connection was fixed (by taking NAC), my back got stabilized. Flow of cerebrospinal fluid is better, CSF-contacting neurons started doing their job and sensory nerves at the concave side healed and started supporting my back. I know this because I felt the nerves growing. I had itch for months before my nerves were healed. Afterwards I felt like everyone was cheating the game all the time and now finally I understood the rules of being upright. For me it works, even 27 years after fusion T3 - L2. But you have to love Pubmed and do your own research if you want to help yourself without being able to talk to a bone surgeon... oops... spine doctor.

Hi. That sounds promising. Are you saying your neuro condition caused your concave side and now it is improved? Do you have radiographers showing this?

How did you know what dose to take? I don't think there are any studies involving humans.

[Rosita]

Hi. That sounds promising. Are you saying your neuro condition caused your concave side and now it is improved? Do you have radiographers showing this?

How did you know what dose to take? I don't think there are any studies involving humans.

Hi, I deleted my post, because I'm not a doctor and I can't help anyone who wants to try the same thing. But yes, I'm still feeling great and in my opinion my concave side is improved.
NAC is used for loads of other things. I checked other researches on Pubmed and toke a sample of what was used there. Then I just tried and after some time found the right dose for me. I still take it, since the improvement gets lost when I stop for too long.

My radiographs? Well, I have a spinal fusion, there isn't much to see. And that is one of the problems. I'm feeling great, but I can't prove a lot. In the future I'm planning to write things out and maybe contact a fundamental researcher.

Edit: I combine this with pilates and scoliosis specific exercises.

[Pooka1]

My radiographs? Well, I have a spinal fusion, there isn't much to see. And that is one of the problems. I'm feeling great, but I can't prove a lot. In the future I'm planning to write things out and maybe contact a fundamental researcher.

Edit: I combine this with pilates and scoliosis specific exercises.

You seem to be saying your actual curve magnitude isn't changing because you are fused but the PT is affecting your soft tissue such that you look less concave, yes? That is not crazy in my lay opinion.