Wnt1 Inducible Signaling Pathway Protein 1 (WISP1) Blocks Neurodegeneration through Phosphoinositide 3 Kinase/Akt1 and Apoptotic Mitochondrial Signaling Involving Bad, Bax, Bim, and Bcl-xL

Abstract

Wnt1 inducible signaling pathway protein 1 (WISP1) is a member of the CCN family of proteins that determine cell growth, cell differentiation, immune system activation, and cell survival in tissues ranging from the cardiovascular-pulmonary system to the reproductive system. Yet, little is known of the role of WISP1 as a neuroprotective entity in the nervous system. Here we demonstrate that WISP1 is present in primary hippocampal neurons during oxidant stress with oxygen-glucose deprivation (OGD). WISP1 expression is significantly enhanced during OGD exposure by the cysteine-rich glycosylated protein Wnt1. Similar to the neuroprotective capabilities known for Wnt1 and its signaling pathways, WISP1 averts neuronal cell injury and apoptotic degeneration during oxidative stress exposure. WISP1 requires activation of phosphoinositide 3-kinase (PI 3-K) and Akt1 pathways to promote neuronal cell survival, since blockade of these pathways abrogates cellular protection. Furthermore, WISP1 through PI 3-K and Akt1 phosphorylates Bad and GSK-3β, minimizes expression of the Bim/Bax complex while increasing the expression of Bcl-xL/Bax complex, and prevents mitochondrial membrane permeability, cytochrome c release, and caspase 3 activation in the presence of oxidant stress. These studies provide novel considerations for the development of WISP1 as an effective and robust therapeutic target not only for neurodegenerative disorders, but also for disease entities throughout the body.

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“…As a potential novel therapeutic target for AD, WISP1 has been shown to prevent neuronal death during oxidative stress [10,11] and block Aβ toxicity in microglia (13). Although multiple cellular pathways may account for the cytoprotective capacity of WISP1 [7,8,10,11,20,21], recent work suggests that mTOR may play a significant role in providing cellular protection with WISP1 [13].…”

“…Although multiple cellular pathways may account for the cytoprotective capacity of WISP1 [7,8,10,11,20,21], recent work suggests that mTOR may play a significant role in providing cellular protection with WISP1 [13]. Yet, cellular protection by mTOR may require a level of modulation since high mTOR activity has been associated with apoptotic cell death [43].…”

“…WISP1 has been demonstrated to rely upon the phosphorylation and activation of phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7,8,10,11,20,21] as well as the mammalian target of rapamycin (mTOR) [13] to promote cellular protection. In addition, mTOR phosphorylates and activates p70S6K at threonine 389 and is a marker of mTOR activity [40].…”

“…WISP1 has a cytoprotective role during bone repair [5], renal injury [6,7], cardiac cell injury [8], and lung epithelial cell damage [9]. Interestingly, WISP1 has been shown to be protective against oxidative stress in neurons [10][11][12] and to block amyloid toxicity in inflammatory microglia of the brain [13]. Protection of central nervous system microglia may foster immune mediated therapies to limit Aβ accumulation and sequester Aβ [14][15][16][17][18][19].…”

“…WISP1 promotes cytoprotection in multiple cell types through pathways that not only require phosphatidylinositol-3-kinase (PI 3-K) and protein kinase B (Akt) [7,8,10,11,20,21], but also utilize pathways in microglia that involve the mammalian target of rapamycin (mTOR) and the proline rich Akt substrate 40 kDa (PRAS40) [13]. mTOR is the catalytic component of two mTOR complexes termed mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [22,23].…”