Microarray gene expression profiling of neural tissues in bovine spastic paresis

Abstract

BackgroundBovine Spastic Paresis (BSP) is a neuromuscular disorder which affects both male and female cattle. BSP is characterized by spastic contraction and overextension of the gastrocnemious muscle of one or both limbs and is associated with a scarce increase in body weight. This disease seems to be caused by an autosomal and recessive gene, with incomplete penetration, although no genes clearly involved with its onset have been so far identified. We employed cDNA microarrays to identify metabolic pathways affected by BSP in Romagnola cattle breed. Investigation of those pathways at the genome level can help to understand this disease.ResultsMicroarray analysis of control and affected individuals resulted in 268 differentially expressed genes. These genes were subjected to KEGG pathway functional clustering analysis, revealing that they are predominantly involved in Cell Communication, Signalling Molecules and Interaction and Signal Transduction, Diseases and Nervous System classes. Significantly enriched KEGG pathway’s classes for the differentially expressed genes were calculated; interestingly, all those significantly under-expressed in the affected samples are included in Neurodegenerative Diseases. To identify genome locations possibly harbouring gene(s) involved in the disease, the chromosome distribution of the differentially expressed genes was also investigated.ConclusionsThe cDNA microarray we used in this study contains a brain library and, even if carrying an incomplete transcriptome representation, it has proven to be a valuable tool allowing us to add useful and new information to a poorly studied disease. By using this tool, we examined nearly 15000 transcripts and analysed gene pathways affected by the disease. Particularly, our data suggest also a defective glycinergic synaptic transmission in the development of the disease and an alteration of calcium signalling proteins. We provide data to acquire knowledge of a genetic disease for which literature still presents poor results and that could be further and specifically analysed in the next future. Moreover this study, performed in livestock, may also harbour molecular information useful for understanding human diseases.

Frameshift Variant in Novel Adenosine-A1-Receptor Homolog Associated With Bovine Spastic Syndrome/Late-Onset Bovine Spastic Paresis in Holstein Sires

“…Presumably, LOC10084876 plays a role in the direct dopamine pathway (Glukhova et al, 2017;Stockwell et al, 2017). That agrees with the accepted neuronal background for BSP and BSS (Gentile and Testoni, 2006;Pariset et al, 2013;De Vlamynck et al, 2014;Goeckmann et al, 2016Goeckmann et al, , 2018. Assuming adenosine-A1-receptor activity for LOC10084876, the supposed affected cell type could be the medium spiny neuron (D1type) (direct pathway MSN) of the dorsal corpus striatum in the forebrain.…”

“…Pariset et al also mentioned Morbus Parkinson, Chorea Huntington, and other human diseases after RNA expression analyses in BSP-affected animals (Pariset et al, 2013) and parkinsonism was already described in forms of HSP (Novarino et al, 2014;Boutry et al, 2019). Hyperekplexia in humans, a disease likewise mentioned by Pariset et al, was identified to cause altered gamma aminobutyric acid concentration in cerebrospinal fluid (Dubowitz et al, 1992).…”

“…The genetic background of BSS/late-onset BSP seems to affect the brain's dopamine or GABA metabolism. Several therapeutics for HSP or other spasms target these pathways, like Baclofen, botulinum toxin, benzodiazepines, and others (Casari and Marconi, 2006;Schwenk et al, 2010;Geng et al, 2013;Pariset et al, 2013;Van Lith et al, 2019). Unfortunately, due to the German (and maybe all international) drug law, none of these drugs is authorized for foodproducing animals.…”

“…Further, neuronal blocks of γefferent nerves by epidural administration of a 0.38% procaine solution interrupt clinical signs temporally (De Vlamynck et al, 2013). An RNA expression study of BSP in Romagnola cattle enforced the hypothesis of a neurodegenerative disease of glycinergic and dopaminergic pathways and showed significant differences in the expression of genes, which are known from hyperekplexia, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease in man (Pariset et al, 2013). However, none of these studies support BSP as a model for multiple sclerosis.…”

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias

“…Interestingly, a lower concentration of homovanillic acid was found in the cerebrospinal fluid of affected calves, indicating that dopamine metabolism is reduced in the CNS ( 68 ). Recent cDNA microarray data, performed on spinal cords of BoSP and healthy calves of a Romagnola cattle breed pointed to a possible alteration of calcium signaling proteins ( 69 ). However, the etiology and pathogenesis of BoSP remain unknown.…”