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Review
, 23 (2), 223-30

Role of Calcineurin in Neurodegeneration Produced by Misfolded Proteins and Endoplasmic Reticulum Stress

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Review

Role of Calcineurin in Neurodegeneration Produced by Misfolded Proteins and Endoplasmic Reticulum Stress

Abhisek Mukherjee et al. Curr Opin Cell Biol.

Abstract

A hallmark event in neurodegenerative diseases is the accumulation of misfolded aggregated proteins in the brain leading to neuronal dysfunction and disease. Compelling evidence suggests that misfolded proteins damage cells by inducing endoplasmic reticulum (ER) stress and alterations in calcium homeostasis. Changes in cytoplasmic calcium concentration lead to unbalances on several signaling pathways. Recent data suggest that calcium-mediated hyperactivation of calcineurin (CaN), a key phosphatase in the brain, triggers synaptic dysfunction and neuronal death, the two central events responsible for brain degeneration in neurodegenerative diseases. Therefore, blocking CaN hyper-activation might be a promising therapeutic strategy to prevent brain damage in neurodegenerative diseases.

Figures

Figure 1
Figure 1. Reversible and Irreversible activation of calcineurin
CaN can be activated reversibly in presence of Ca2+/CaM up to 15 times. This seems to happen during chronic elevation of Ca2+ in the cytoplasm resulting from ER stress after exposure to misfoled proteins. CaN can also be activated irreversibly by proteolytic cleavage of the CnAI and CaM binding domains. This cleaved form of the enzyme is no longer sensitive to Ca2+/CaM and thus constitutively active.
Figure 2
Figure 2. Role of chronically activated CaN in neuronal death
Chronically activated CaN has been implicated in neuronal death at least in three major ways: (1) Dephosphorylation of BAD, releasing it from the scaffolding protein 14-3-3, leading to apoptotic activity; (2) Aberrant dephosphorylation of the cytoplasmic subunit of NFAT (NFATc) induces its translocation to the nucleus where interact with NFATn, leading to chronic induction of NFAT regulated genes; (3) Dephosphorylation of Hunt ingtin result in a partial loss of function of this protein leading to impaired vesicular transport, especially of various growth factors, including BDNF.
Figure 3
Figure 3. Role of chronically activated CaN in synaptic dysfunction
CaN has been implicated in synaptic abnormalities during neurodegenerative disorders at least in three different ways: (1) Activated CaN dephosphorylates CREB inhibiting its translocation to the nucleus, resulting in the abnormal shut off of CREB regulated gene expression required for neuronal growth and synaptic plasticity; (2) CaN mediates the internalization of AMPA receptor bound to misfolded proteins (particularly Aβ oligomers) inducing synaptic disruption and inhibition of long term potentiation; (3) Inhibition of neurotransmitter release by abrogating synaptic vesicle transport through dephosphorylaton of synapsin I.

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