Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3

نویسندگان

  • Minako Tateno
  • Shinsuke Kato
  • Takashi Sakurai
  • Nobuyuki Nukina
  • Ryosuke Takahashi
  • Toshiyuki Araki
چکیده

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we demonstrated that, starting from the pre-onset stage of FALS, misfolded SOD1 species associates specifically with kinesin-associated protein 3 (KAP3) in the ventral white matter of SOD1(G93A)-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargos including choline acetyltransferase (ChAT). Motor axons in SOD1(G93A)-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. By employing a novel FALS modeling system using NG108-15 cells, we showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species. Furthermore, such impairment was able to be normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in human FALS cases as well. These results suggest that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the dysfunction of ALS.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Deprenyl increases synaptophysin and choline acetyltransferase in rat after sciatic nerve axotomy

Neuroprotective effect of deprenyl on motoneurons of spinal cord after axotomy of peripheral nerves such as sciatic has been well established. Deprenyl is an inhibitor of monoamine oxidase type-B (MAO-B). The main function of this agent is the release of neurotransmitters from pre-synaptic terminals. Acetylcholine is a neurotransmitter that is synthesized by choline acetyltransferase (ChAT) and...

متن کامل

Deprenyl increases synaptophysin and choline acetyltransferase in rat after sciatic nerve axotomy

Neuroprotective effect of deprenyl on motoneurons of spinal cord after axotomy of peripheral nerves such as sciatic has been well established. Deprenyl is an inhibitor of monoamine oxidase type-B (MAO-B). The main function of this agent is the release of neurotransmitters from pre-synaptic terminals. Acetylcholine is a neurotransmitter that is synthesized by choline acetyltransferase (ChAT) and...

متن کامل

Stress-related effects on neuronal morphology and choline acetyltransferase activity in the hippocampus

The effects of semi-chronic stress on neuronal morphology and choline acetyltransferase were studied by injecting rats with dexamethasone. It was found that in the dexamethasone-treated rats the choline acetyltransferase activity had increased in the area where the fibers from the perforant pathway synapse with the granular cell layer of the dentate gyrus and also where the mossy fibers of the ...

متن کامل

Stress-related effects on neuronal morphology and choline acetyltransferase activity in the hippocampus

The effects of semi-chronic stress on neuronal morphology and choline acetyltransferase were studied by injecting rats with dexamethasone. It was found that in the dexamethasone-treated rats the choline acetyltransferase activity had increased in the area where the fibers from the perforant pathway synapse with the granular cell layer of the dentate gyrus and also where the mossy fibers of the ...

متن کامل

Kinesin-2 differentially regulates the anterograde axonal transports of acetylcholinesterase and choline acetyltransferase in Drosophila.

Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) are involved in acetylcholine synthesis and degradation at pre- and postsynaptic compartments, respectively. Here we show that their anterograde transport in Drosophila larval ganglion is microtubule-dependent and occurs in two different time profiles. AChE transport is constitutive while that of ChAT occurs in a brief pulse durin...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Human Molecular Genetics

دوره 18  شماره 

صفحات  -

تاریخ انتشار 2009