Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1

Abstract

Spinocerebellar Ataxia Type 1 (SCA1) is an incurable, dominantly inherited neurodegenerative disease of the cerebellum caused by a polyglutamine-repeat expansion in the protein ATXN1. While analysis of human autopsy material indicates significant glial pathology in SCA1, previous research has focused on characterizing neuronal dysfunction. In this study, we characterized astrocytic and microglial response in SCA1 using a comprehensive array of mouse models. We have discovered that astrocytes and microglia are activated very early in SCA1 pathogenesis even when mutant ATXN1 expression was limited to Purkinje neurons. Glial activation occurred in the absence of neuronal death, suggesting that glial activation results from signals emanating from dysfunctional neurons. Finally, in all different models examined glial activation closely correlated with disease progression, supporting the development of glial-based biomarkers to follow disease progression.

RNAi prevents and reverses phenotypes induced by mutant human ataxin‐1

“…23 We also noted enhanced Iba1 + immunoreactivity in control treated B05 mice relative to WT animals, and qualitatively more in the 8×10 10 vg rAAV1.miS1 treatment group. In B05 mice treated with 8×10 8 or 8×10 9 vg, Iba1 + immunoreactivity was reduced.…”

Mutant ataxin1 disrupts cerebellar development in spinocerebellar ataxia type 1

“…Surprisingly, there was significantly less GFAP staining in the granular layer of Sca1 154Q/2Q cerebella than in control cerebella at both P18 and 5 months of age (Figure 8A), the same time points at which we had observed exaggerated GABAergic BC innervation. These changes are distinct from the increased GFAP staining we observed in reactive Bergmann glia (Supplemental Figure 5, A and B) (39). Strikingly, the velate astrocytes isolated from Sca1 154Q/2Q cerebella had lower proliferative capacity than astrocytes from controls (Supplemental Figure 6, A and B).…”

“…Indeed, several studies have shown that the ablation of astrocytes or the presence of abnormal astrocytes in the developing or adult cerebellum causes loss of PCs or cerebellar atrophy (47)(48)(49). A developmental decrease in velate astrocytes and high reactivity of Bergmann glial cells in SCA1 might also alter the inflammatory response (39,50). We do not know why the Bergmann glial astrocytes and velate astrocytes adopt different fates in SCA1, but it is possible that these 2 populations are influenced by other signals.…”

“…, and ATXN1[82Q] mice has been described previously (4,39,54). The Sca1 154Q/2Q line was generated by knocking 154 CAG repeats into the mouse locus with a small flanking region derived from a human sequence (but conserved in mice).…”

Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy

“…Microglia are the major immune cells in the central nervous system (CNS) and are responsible for adjusting synapses, removing cellular debris and mediating the inflammatory response (42). In spinocerebellar ataxia (SCA) mouse models, the degree of microglia activation follows disease progression and correlates with the severity of damage and neuronal loss within the affected region of the CNS (43). Microglia activation has been observed in several neurodegenerative diseases including Alzheimer’s (44), Parkinsons (45) and amyotrophic lateral sclerosis (46) (47), therefore a potential role of microglia activation in equine CA was expected.…”