Oncogenic PAK/ERK-Synapsin-GABA Signaling: A Common Link in LD of Down Syndrome and NF1

Old drug Pentylenetetrazole (PTZ) and Bio 30 may improve learning and memory
in Down Syndrome (DS) and other LD victims such as NF1 children

Recently Alcino Silva's group at UCLA found that NF1 model of mice which
is associated with memory deficit or LD (Learning Deficit/Disability) is
in part due to the abnormal release of GABA, which is caused by ERK-mediated
phosphorylation of synapsin 1, and a GABA antagonist called picrotoxin can
reverse the LD symptom of NF1 mice.

Interestingly, in 2002 Yasuharu Sasaki's group at Kitasato University in Japan demonstrated that PAK1 phosphorylates synapsin 1 at Ser 603. It is also known that PAK1 activates the kinase ERK through the kinases Raf and MEK.

In other words, abnormal activation of PAK1 in NF1 patients also could cause an excess release of GABA through the phosphorylation of synapsin 1 by either stimulating the kinase Erk or its direct action on Ser 603, and anti-PAK1 drugs such as Bio 30 could improve the impaired learning ability of NF1 children, in addition to suppression of the growth of NF1 tumors such as MPNST.

Similarly, in 2007 a group led by Craig Garner, a director of the Down Syndrome
Research Center at Stanford University, found that an old drug called PTZ
(Pentylentetrazole) improves the impaired learning ability of DS model of
mice. PTZ was once used as an epilepsy drug, and antagonizes GABA as does
picrotoxin.

These findings altogether suggest a common cause, PAK/ERK-synapsin-GABA link,
in LD of DS and NF1.

Thus, US researchers are now considering a clinical trial to test whether PTZ
has a similar effect in humans with Down syndrome or NF1.


Oncogenicity of GABA!

More interestingly, in 2007 Hidewaki Nakagawa's group at Tokyo University
(IMS) found that GABA (gamma-Aminobytyric acid) A receptor is over-expressed
in pancreatic cancers, and GABA promotes the growth of pancreatic cancer
cells by stimulating ERK. Thus, there is an oncogenic vicious cycle of ERK
and GABA which activate each other. Anti-PAK1 drugs that block the PAK1-mediated
ERK activation could suppress this vicious cycle.

Thus, it wouldn't be a great surprise that more than two decades ago, a Japanese
couple of scientists (called Furusawa) at University of Hawaii reported
that PTZ, a GABA antagonist, indeed suppresses the growth of a few cancers
such as LLC (Lewis Lung Carcinoma) xenografts in mice, presumably by blocking
the GABA signaling. By the way, PTZ is an alkaloid from Narcissus flower (水仙)。