Park2-Null/Tau Transgenic Mice Reveal a Functional Relationship between Parkin and Tau

Abstract

Mutations, haplotypes, and polymorphisms of tau and Park-2 genes constitute risk factors for developing tauopathies. In order to analyze the possible relationship between parkin and tau we generated a double-mutant mouse deficient for Park-2 expression and overexpressing a mutant tau protein (hTauVLW). Mice develop normally, although the median survival rate is considerably reduced with respect to wild type (45%). Aggregates of phosphorylated tau in neurons and reactive gliosis are quite abundant in cortex and hippocampus of these mice. Moreover, while in young transgenic mice the hTauVLW immunostained transgene product is observed in both cell bodies and dendrites, the hTauVLW mutant protein is only detected in the neuronal cell bodies when Park-2 gene is additionally deleted. Moreover, DNA fragmentation was detected by the TUNEL method, and cerebral atrophy is also present in these regions. The levels of phosphorylated tau and Hsp70 are increased in the double-mutant mice, while CHIP expression in hippocampus is lower when the Park-2 gene is deleted. Thus, the combination of Park-2 gene deletion with hTauVLW transgene overexpression in mice produces serious neuropathological effects, which reflect the existence of some relationship between both proteins.

Genetic analysis of Parkin in early onset Parkinson's disease (PD): Novel intron 9 g > a single nucleotide polymorphism and risk of Taiwanese PD

“…This is consistent with the reported significant association of homozygous V380 with sporadic PD [L€ ucking et al, 2003]. As a functional relationship between Parkin and tau existed [Guerrero et al, 2008], the reported association of 380L with less risk of taupathy progressive supranuclear palsy [Ros et al, 2008] also suggests the functional significance of this variation. Further studies are needed to clarify if and how this polymorphism predisposes to PD.…”

Development of Tau Aggregation Inhibitors for Alzheimer's Disease

“…[12,13] The most common tauopathy is Alzheimers disease, but tau deposits also occur in frontotemporal dementias , Picks disease, Parkinsons disease, progressive nuclear palsy, and other conditions. [14,15] In Alzheimers disease, the brain contains two types of aggregates: intracellular neurofibrillary tangles (tau protein) and extracellular senile or "amyloid" plaques consisting of the Ab peptide, a cleavage product of the membrane protein APP. [16] Both types of aggregates are toxic for neurons, and both are based on the principle of amyloid aggregation, in which fibers are formed from the subunit protein by axial stacking of b strands, generating a cross-b-sheet structure at the core of the filaments.…”

Parkinson’s Disease and Parkin: Insights from Park2 Knockout Mice

“…In one study, KaplanMeier survival analysis using the Park2 tm1Roo knockout model suggested an increase in mortality, which is consistent with data from PD patients' pre-L-DOPA therapy (RodriguezNavarro et al, 2007). However, in another study using the Park2 tm1Roo knockout model on a different background a difference in survival was not found (Guerrero et al, 2008). A reduction in body weight was identified in three lines but was not replicated in three other lines (Table 2) (Itier et al, 2003;Oyama et al, 2010;Palacino et al, 2004;Perez and Palmiter, 2005;Von Coelln et al, 2004;Zhu et al, 2007).…”