Overexpression of Human SOD1 Leads to Discrete Defects in the Cerebellar Architecture in the Mouse

Abstract

The human superoxide dismutase 1 (SOD1) gene is responsible for neutralizing supercharged oxygen radicals within the cell. Mutation in SOD1 gene causes amyotrophic lateral sclerosis (ALS). Recent studies have shown involvement of the cerebellum in ALS, although the cerebellar contribution in SOD1 transgenic mice remains unclear. Using immunohistopathology, we investigated the Purkinje cell phenotype in the vermis of the SOD1 transgenic mice cerebellum. Calbindin 1 (Calb1) and three well-known zone and stripe markers, zebrin II, HSP25, and PLCβ4 have been used to explore possible alteration in zone and stripe. Here we show that Calb1 expression is significantly reduced in a subset of the Purkinje cells that is almost aligned with the cerebellar zones and stripes pattern. The Purkinje cells of SOD1 transgenic mice display a pattern of Calb1 down-regulation, which seems to proceed to Purkinje cell degeneration as the mice age. The onset of Calb1 down-regulation in Purkinje cells begins from the central zone and continues into the nodular zone, however it has not been observed in the anterior and posterior zones. In a subgroup of SOD1 transgenic mice in which gait unsteadiness was apparent, down-regulation of Calb1 is seen in a subset of PLCβ4+ Purkinje cells in the anterior zone. These observations suggest that the Calb1− subset of Purkinje cells in the anterior zone, which receives somatosensory input, causes unsteady gait. Our data suggest that human SOD1 overexpression leads to Calb1 down-regulation in the zone and strip pattern and raise the question of whether SOD1 overexpression leads to Purkinje cells degeneration.

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

“…3a ). As Purkinje cells of the cerebellum play a key role in regulating and coordinating movement and have been found to be affected in ALS 39 – 42 , we wanted to see if Purkinje cells were degenerated in Matr3 S85C/S85C mice. Intriguingly, immunostaining of the cerebellum with anti-calbindin antibody showed an extensive loss of Purkinje cells in Matr3 S85C/S85C mice (Fig.…”

Tremor in motor neuron disease may be central rather than peripheral in origin

“…Structural and functional cerebellar abnormalities in ALS have recently been demonstrated by imaging and pathological studies, especially in patients with ALS with abnormal repeat expansions in the C9orf72 and ataxin‐2 genes (ATXN2) . None of our patients with MND presented with cerebellar signs or were tested for intermediate ATXN2 expansions but, in one patient, C9orf72 mutation was not found and one patient carried a mutation in the SOD1 gene, whose overexpression leads to Purkinje cell degeneration in mice .…”

“…Correspondence: K. P. Bhatia, University College London, 33 Queen Square, London WC1N 3BG, UK (tel. : 44 20 3448 8723; fax: 44 20 3448 3954; e-mail: k.bhatia@ucl.ac.uk).…”

SOD1 stimulates lamellipodial protrusions in Neuro 2A cell lines

“…Regulatory mechanisms normally preventing toxicity of WT SOD1 at basal expression levels might be unable to operate in conditions of overexpression. In line with this possibility, neuronal tissue abnormalities have been reported in WT SOD1 transgenic mice [19], and abnormally high levels of SOD1 transcripts were reported in spinal cord, brain stem and lymphocytes of sporadic ALS patients [20], although it remains to be investigated whether these conditions are associated to overstimulation of Rac1-mediated pathway for lamellipodia.…”