Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration

Abstract

The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles. Although mouse models have been created by overexpressing specific proteins including beta-amyloid precursor protein, presenilin and tau, no model has been generated by gene knockout. Phosphorylation of tau and other proteins on serine or threonine residues preceding proline seems to precede tangle formation and neurodegeneration in Alzheimer's disease. Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase. Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation, which suggests that Pin1 is involved in neurodegeneration; however, genetic evidence is lacking. Here we show that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in Alzheimer's disease. Pin1 knockout in mice causes progressive age-dependent neuropathy characterized by motor and behavioural deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies.

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

“…Whereas it is possible that the inherent properties of mouse tau may make it resistant to filament formation, mice deficient in Pin1, an enzyme shown to be critical for dephosphorylation of tau, and mice engineered to have increased activation of Cdk5 both accumulate phosphorylated endogenous mouse tau and develop argyrophilic tau aggregates (Liou et al, 2003;Noble et al, 2003). Although ubiquitin immunoreactivity was not assessed in either of these models, our findings of robust phospho-tau accumulation in CHIP Ϫ/Ϫ and CHT mice without any detectable argyrophilic pathology implies that CHIP may function to relieve neurons of potentially toxic properties of soluble phospho-tau intermediates through facilitation of its degradation and/or perhaps promotion of aggregation.…”

CRMP5 (Collapsin Response Mediator Protein 5) Regulates Dendritic Development and Synaptic Plasticity in the Cerebellar Purkinje Cells

“…2). This behavioral disorder may suggest the impairment of the CNS (Liou et al, 2003;Chen et al, 2005;Komatsu et al, 2006).…”

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…However, it is noteworthy that the repeat domain possesses two motifs of the consensus type KVERQ, which interact with hsc70 for chaperonemediated autophagy (Wang et al 2009). Other interactors of Tau are linked to chaperone components, for example the prolyl isomerase Pin-1 (Liou et al 2003), FKBP51, FKBP52 (Chambraud et al 2010;Jinwal et al 2010). Pin-1 isomerizes the motifs pT212-P and pS231-P in the proline-rich domain from cis to trans and thus allows the dephosphorylation by PP-2a and recovery of microtubule binding (Smet et al 2004).…”