RESUMO
Amyotrophic lateral sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that amyotrophic lateral sclerosis is part of a spectrum of disorders, ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic lateral sclerosis Type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localized to the cytoplasmic surface of the endoplasmic reticulum, where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of amyotrophic lateral sclerosis Type 8 based on the VapBP56S mutation and VapB gene deletion has been generated in rats. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of amyotrophic lateral sclerosis Type 8. A loss of motor neurones in VapBP56S/+ and VapBP56S/P56S animals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB-/- animals exhibit a relative increase in cytoplasmic TDP-43 levels compared with the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapBP56S/+ , VapBP56S/P56S and VapB-/- animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extramotor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of amyotrophic lateral sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.
RESUMO
MECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis in Mecp2 -/y and Mecp2 -/+ . Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction.