p21-activated kinase 1 promotes soluble mutant huntingtin self-interaction and enhances toxicity

Abstract

Huntington's disease (HD) is caused by a polyglutamine (polyQ) expansion in the huntingtin (htt) protein. While aggregation is a pathological hallmark of HD and related polyQ expansion diseases, the role of aggregates has been disputed. Here we report that p21-activated kinase 1 (Pak1) binds to htt in vivo and in vitro. Pak1 colocalized with mutant htt (muhtt) aggregates in cell models and in human HD brains. Pak1 overexpression enhanced the aggregation of muhtt. Furthermore, we observed SDS-soluble wild-type htt (wthtt)-wthtt, wthtt-muhtt and muhtt-muhtt interactions, which were enhanced by the presence of Pak1. We show that Pak1 overexpression enhanced htt toxicity in cell models and neurons in parallel with its ability to promote aggregation, while Pak1 knockdown suppressed both aggregation and toxicity. Overexpression of either kinase-dead or wild-type Pak enhanced both aggregation and toxicity. Our data reveal a novel mechanism regulating muhtt oligomerization and toxicity and suggest that pathology may be at least partly dependent on soluble muhtt-muhtt interactions.

Huntingtin promotes cell survival by preventing Pak2 cleavage

“…4B). These data are consistent with those for the wild-type Htt-Pak1 or muHtt-Pak1 interactions (Luo et al, 2008).…”

“…However, much of the research on the normal functions of Htt has been restricted to neuronal systems, even though many of its normal functions might be generic. We previously reported that Pak1 binding to Htt promotes Htt-Htt interaction, and thus enhances muHtt oligomerisation and toxicity (Luo et al, 2008). Pak1, Pak2 and Pak3 have highly conserved protein sequences and similar functions (Bokoch, 2003).…”

“…Accordingly, we investigated the issue of whether other kinases or their substrates can bind Htt. Using immunoprecipitation, we found that Pak1 is an Htt-binding protein and that Htt interacts with the Pak1 C-terminus (Luo et al, 2008). As this region is highly conserved between Pak1 and Pak2, we investigated whether Htt also interacts with Pak2.…”

“…Recently, we identified Pak1 as an Htt-binding protein (Luo et al, 2008). Here, we investigated the ability of Htt to physically interact with Pak2 and thus prevent Pak2 cleavage.…”

Effective neurofibromatosis therapeutics blocking the oncogenic kinase PAK1

“…In addition, there are several other non-cancerous diseases which also require PAK1 (67,68,(73)(74)(75)(76)(77)(78)(79)(80)(81): Among them are AIDS (HIV-infection), malaria, Alzheimer's (AD), Huntington's (HD), infl ammatory diseases (asthma and arthritis), insulin-resistant diabetes (type 2), obesity, hypertension, seizures such as epilepsy, autistic diseases such as Fragile X syndrome, and learning defi cit (LD). Thus, propolis and other PAK1 blockers would serve as the effective (and safe) therapeutics for these diseases as well.…”