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Related Concept Videos

Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
Postsynaptic Potential (PSP)01:32

Postsynaptic Potential (PSP)

Postsynaptic potential (PSP) refers to a change in the electrical potential of a neuron when neurotransmitters released by presynaptic neurons bind to postsynaptic receptors. This potential can either be excitatory, leading to depolarization and ultimately action potential generation, or inhibitory, leading to hyperpolarization and suppression of the postsynaptic neuron.
There are two types of receptors: ionotropic and metabotropic.
The ionotropic receptor is the membrane protein that has an...

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CSPα knockout causes neurodegeneration by impairing SNAP-25 function.

Manu Sharma1, Jacqueline Burré, Peter Bronk

  • 1Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. sharma11@stanford.edu

The EMBO Journal
|December 22, 2011
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Neurodegeneration in cysteine-string protein-α knockout mice is caused by reduced SNAP-25 levels, impairing SNARE-complex assembly. Restoring SNAP-25 function rescues this neurodegenerative phenotype.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Cysteine-string protein-α (CSPα) is a synaptic vesicle protein acting as a co-chaperone for the SNARE protein SNAP-25.
  • CSPα knockout (KO) leads to severe neurodegeneration, which is paradoxically rescued by α-synuclein.
  • CSPα KO reduces SNAP-25 levels and impairs SNARE-complex assembly, with α-synuclein only rescuing the latter.

Purpose of the Study:

  • To investigate whether the neurodegeneration in CSPα KO mice results from decreased SNAP-25 function or other uncharacterized CSPα targets.
  • To determine the precise role of SNAP-25 levels and SNARE-complex assembly in CSPα KO-induced neurodegeneration.

Main Methods:

  • Utilized CRISPR-Cas9 gene editing for SNAP-25 knockout and shRNA for knockdown in CSPα KO mice.
  • Employed overexpression of wild-type and mutant SNAP-25 to assess rescue effects.
  • Correlated neurodegenerative phenotypes with levels of SNAP-25 and SNARE-complex assembly.

Main Results:

  • Decreasing SNAP-25 levels in CSPα KO mice exacerbated the neurodegenerative phenotype.
  • Overexpression of functional SNAP-25 rescued the neurodegeneration, while inactive mutants did not.
  • Neurodegeneration severity directly correlated with the extent of SNARE-complex assembly impairment.

Conclusions:

  • Neurodegeneration in CSPα KO mice is primarily driven by defective SNAP-25 function, leading to impaired SNARE-complex assembly.
  • SNARE-complex assembly is the critical downstream effector linking SNAP-25 dysfunction to neurodegeneration.
  • CSPα's role in maintaining synaptic function is largely mediated through its regulation of SNAP-25 and subsequent SNARE complex formation.