Vascular regression precedes motor neuron loss in the FUS (1-359) ALS mouse model

Abstract

Amyotrophic lateral sclerosis (ALS) presents a poorly understood pathogenesis. Evidence from patients and mutant SOD1 mouse models suggests vascular damage may precede or aggravate motor dysfunction in ALS. We have previously shown angiogenin (ANG) treatment enhances motor neuron survival, delays motor dysfunction and prevents vascular regression in the SOD1G93A ALS model. However, the existence of vascular defects at different stages of disease progression remains to be established in other ALS models. Here, we assessed vascular integrity in vivo throughout different disease stages, and investigated whether ANG treatment reverses vascular regression and prolongs motor neuron survival in the FUS (1-359) mouse model of ALS. Lumbar spinal cord tissue was collected from FUS (1-359) and non-transgenic control mice at postnatal day (P)50, P90 and P120. We found a significant decrease in vascular network density in lumbar spinal cords from FUS (1-359) mice by day 90, at which point motor neuron numbers were unaffected. ANG treatment did not affect survival or counter vascular regression. Endogenous Ang1 and Vegf expression were unchanged at P50 and P90; however, we found a significant decrease in miRNA 126 at P50, indicating vascular integrity in FUS mice may be compromised via an alternative pathway. Our study demonstrates that vascular regression occurs before motor neuron degeneration in FUS (1-359) mice, and highlights that heterogeneity in responses to novel ALS therapeutics can already be detected in preclinical mouse models of ALS..

5′ValCAC tRNA fragment generated as part of a protective angiogenin response provides prognostic value in amyotrophic lateral sclerosis

“…To determine whether 5′ValCAC levels were altered in a second ALS model, we employed the FUS (1-359) mouse model ( Shelkovnikova et al , 2013 ) from which spinal cord tissue and serum samples were available. FUS (1-359) TG mice overexpress a truncated human FUS gene lacking a nuclear localization signal, which is prone to cytoplasmic aggregation, and show an early vasculature defect similar to the SOD1 G93A model ( Crivello et al , 2018 , 2019 ). We analysed mice collected at post-natal day 90 which equates to around symptom onset as the average lifespan of TG mice from the FUS (1-359) colony is 120 days (±22 days)( Hogg et al , 2017 ).…”

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

“…In addition, FUS protein can regulate the serine‐threonine protein kinase (Ak strain transforming, Akt) and forkhead box O1 (FOXO) proteins, further elements of GSK‐3β cascade that can explain the reported changes in GSK‐3β expression in the FUS‐tg model. Moreover, paracrine secretion by stem cells of trophic factors can ameliorate decreased vascular network density in lumbar spinal cords, a recently demonstrated disease mechanism in employed here FUS‐tg mice, which is sensitive to a therapy with angiogenetic/growth factors . Thus, it might be speculated that the effects of the stem cells might be due to paracrine activities and the release of neurotrophins and anti‐inflammatory cytokines that classical drug therapy cannot provide …”

Stem cell therapy and FUS[1‐359]‐transgenic mice: A recent study highlighting a promising ALS model and a promising therapy

“…The article of de Munter and co‐authors “ Neuro‐Cell therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice ” has shown that their novel approach has beneficial effect in the G93A SOD‐1 mutant and the more recently described FUS[1‐359] ‐transgenic mouse, which confers a number of advantages over “golden standard” SOD‐1‐G93A line. The study employs a new stem cell preparation known as “Neuro‐Cells” (Neuroplast, Netherlands), which are argued to have novel antiinflammatory actions, such as the suppression of microglial activation, as part of their “stem cell” activity.…”