Figure 6
HSP70 expression is increased in brains of AD and PD patients, and especially in AD, neurons with HSP70 nuclear localization exhibit less Aβ accumulation and apoptotic cell death.
(a) ERK activation as well as HSP70 and VRK3 expression were increased in the prefrontal cortex (PFC) of AD and PD patients compared with non-demented control individuals. (b) Quantification of HSP70, VRK3 and p-ERK in AD, PD, and control brains as in (a). Values are normalized to GAPDH and shown as mean ± s.d., n = 4. Student’s t-test, *P < 0.05, **P < 0.01. (c) HSP70 nuclear localization prevented Aβ aggregate formation in AD brains. White arrowheads highlight nuclear-localized HSP70. White arrows points cell enlarged. Scale bar, 10 μm. (d) Cytosolic calcium levels are kept low via energy-dependent sequestration into mitochondria and endoplasmic reticulum (not shown). Excessive activation of glutamate receptors and the formation of annular pores consisting of oligomeric Aβ and α-synuclein in the lipid bilayer lead to membrane permeabilization and promote excessive calcium influx. Increased intracellular calcium levels result in calcium overload of mitochondria and activation of the Ras/Raf/ERK pathway. Aβ and other amyloidogenic peptides, such as α-synuclein, generate ROS from molecular oxygen through electron transfer interactions, and impaired oxidative phosphorylation and decreased complex I activity in mitochondria also cause ROS formation ROS further impairs the ubiquitin-proteasome system, leading to accelerated accumulation of protein aggregates. In parallel, loss of mitochondrial membrane potential and persistent activation of the Ras/Raf/ERK pathway result in the release of cytochrome c from the mitochondria into the cytosol, caspase activated, and ultimately, neuronal death occurred. VRK3 facilitated nuclear localization of glutamate-induced HSP70. Nuclear HSP70 inhibited sustained ERK activation through enhancement of VHR phosphatase activity via direct binding and thereby reduced neuronal cell death.
