Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes.

Accumulation of amyloid ß (Aß) and tau represent the two major pathological hallmarks of Alzheimer's disease (AD). Despite the critical importance of Aß accumulation as an early event in AD pathogenesis, multiple lines of evidence indicate that tau is required to mediate Aß-induced neurotoxic signals in neurons. We have previously shown that the scaffolding protein Ran-binding protein 9 (RanBP9), which is highly elevated in brains of AD and AD mouse models, both enhances Aß production and mediates Aß-induced neurotoxicity. However, it is unknown whether and how RanBP9 transmits Aß-induced neurotoxic signals to tau. Here we show for the first time that overexpression or knockdown of RanBP9 directly enhances and reduces tau levels, respectively, in vitro and in vivo. Such changes in tau levels are associated with the ability of RanBP9 to physically interact with tau and heat shock protein 90/heat shock cognate 70 (Hsp90/Hsc70) complexes. Meanwhile, both RanBP9 and tau levels are simultaneously reduced by Hsp90 or Hsc70 inhibitors, whereas overexpression or knockdown of RanBP9 significantly diminishes the anti-tau potency of Hsp90/Hsc70 inhibitors as well as Hsc70 variants (WT & E175S). Further, RanBP9 increases the capacity for Hsp90 and Hsc70 complexes to bind ATP and enhances their ATPase activities in vitro. These observations in vitro and cell lines are recapitulated in primary neurons and in vivo, as genetic reduction in RanBP9 not only ameliorates tauopathy in Tau-P301S mice but also rescues the deficits in synaptic integrity and plasticity.

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation.

Amyloid ß (Aß) accumulation is an early event in the pathogenesis of Alzheimer's disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aß deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aß-induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53-responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro-apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway.

Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity.

Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP-43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP-43 inclusions.