Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.

Roles of tau protein in health and disease

“…R6/2 mice exhibit motor dysfunction and impaired learning and memory and intraneuronal inclusions of mutant huntingtin [99, 292]. Notably, increased tau phosphorylation is evident in the brains of R6/2 mice in parallel with reduced amounts of protein phosphatases [39, 174]. Increased tau phosphorylation has also been shown in HD, along with elevated GSK3 activity [268].…”

The Emerging Roles of the Calcineurin-Nuclear Factor of Activated T-Lymphocytes Pathway in Nervous System Functions and Diseases

“…FK506 abrogated all these alterations. Concomitant tau hyperphosphorylation and calcineurin overactivation were also reported in mouse models of Huntington's disease [41]. On the other hand, IL-6/Janus kinase (JAK) signaling induced neuroprotective anti-NMDA activities in cultured cerebellar granule neurons via calcineurin-dependent inhibition of activities of NMDA receptor subunits NR2B and NR2C and concomitant inhibitions of NMDA-induced L-type voltage-gated Ca 2+ channel activity and intracellular Ca 2+ store release [194].…”

“…Calcineurin/NFAT involvement has also been reported in psychiatric disorders, epilepsy, and traumatic brain and spinal cord injuries [30–35]. Moreover, recent data also suggest that NFAT isoforms are selectively activated in neurons and glial cells in nervous system diseases [36, 37] and animal models [38–41]. …”

Dysregulation of Corticostriatal Connectivity in Huntington’s Disease: A Role for Dopamine Modulation

“…Under normal conditions, the activity of DARPP-32 would be inhibited by calcineurin (phosphatase-2B), but the expression of calcineurin is decreased by about 30% in pre-sympomatic R6/2s and Q175s but further downregulated when motor signs appear [191], suggesting that D 1 receptor signaling might be chronically activated. In support of this view, the expression of immediate early genes, which occurs after chronic activation of D 1 receptors [192], is elevated in R6/2 mice [190], indicating augmented neuronal activity in this model and confirmed by recording of striatal MSNs in behaviorally active R6/2s [112].…”