Renal pathology in a mouse model of severe Spinal Muscular Atrophy is associated with downregulation of Glial Cell-Line Derived Neurotrophic Factor (GDNF)

Abstract

Spinal Muscular Atrophy (SMA) occurs as a result of cell-ubiquitous depletion of the essential SMN protein. Characteristic disease pathology is driven by a particular vulnerability of the ventral motor neurons of the spinal cord to decreased SMN. Perhaps not surprisingly, many other organ systems are also impacted by SMN depletion. The normal kidney expresses very high levels of SMN protein, equivalent to those found in the nervous system and liver, and levels are dramatically lowered by ~ 90–95% in mouse models of SMA. Taken together these data suggest that renal pathology may be present in SMA. We have addressed this using an established mouse model of severe SMA. Nephron number, as assessed by gold standard stereological techniques, was significantly reduced. In addition, morphological assessment showed decreased renal vasculature, particularly of the glomerular capillary knot, dysregulation of nephrin and collagen IV, and ultrastructural changes in the trilaminar filtration layers of the nephron. To explore the molecular drivers underpinning this process, we correlated these findings with quantitative PCR measurements and protein analyses of Glial Cell-Line Derived Neurotrophic Factor (GDNF), a crucial factor in ureteric bud branching and subsequent nephron development. GDNF levels were significantly reduced at early stages of disease in SMA mice. Collectively, these findings reveal significant renal pathology in a mouse model of severe SMA, further reinforcing the need to develop and administer systemic therapies for this neuromuscular disease.

bootGSEA: a bootstrap and rank aggregation pipeline for multi-study and multi-omics enrichment analyses

“…The kidneys were dissected, snap-frozen in liquid nitrogen, and stored at −80°C until analysis. Tissue was lyzed either for RNA-seq or for proteomics analyses, respectively, as described previously ( Allardyce et al, 2020 ; Hensel et al, 2021 ), using total organ and total RNA. All animal experiments were conducted in accordance with the German Animal Welfare law and approved by the Ministry of Food, Agriculture, and Consumer Protection of Lower Saxony (LAVES file no.…”

“…The disease is characterized by the degeneration of motoneurons, with the subsequent atrophy of skeletal muscles to muscular atrophy since the SMN affects all tissues, which also include non-skeletal muscles. Moreover, SMA is a multi-system disorder that also affects peripheral organs, such as the kidney ( Allardyce et al, 2020 ). Three treatment methods are available, all increasing SMN expression.…”

Innovating spinal muscular atrophy models in the therapeutic era

“…Pathologically, they are characterised by varying degrees of motor neuron loss, NMJ pathology and muscle defects ( Le et al, 2005 ; Monani et al, 2000 ; Murray et al, 2008 ). In addition to varying motor pathologies, systemic pathologies affecting almost all organs have also been described in mice ( Allardyce et al, 2020 ; Deguise et al, 2019 ; Šoltić et al, 2019 ; Thomson et al, 2017 ). The severity of such systemic, non-CNS pathology, however, varies extensively between mouse models and depends, at least partially, on the genetic background of the mouse model ( Buettner et al, 2021 ).…”

The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap

“…The inherited neuromuscular disease spinal muscular atrophy (SMA) is primarily characterised by loss of lower motor neurons and subsequent muscular atrophy [ 1 , 2 ]. Preclinical studies in patients and animal models have highlighted systemic aspects of the disease, which have recently been reviewed [ 3 ] and include, for example, impairment of skeletal muscle development [ 4 ], cardiac defects and dysfunction [ 5 , 6 ], detrimental vascular changes [ 7 ], defects in fatty acid metabolism [ 8 ] and altered renal structure and function [ 9 , 10 ]. In more than 95% of cases, SMA is caused by loss of function of the survival of motor neuron 1 ( SMN1 ) gene, resulting in insufficient levels of SMN protein [ 11 ].…”