Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α.

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α).

A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development.

Motorneurons require cysteine string protein-α to maintain the readily releasable vesicular pool and synaptic vesicle recycling.

Cysteine string protein-α (CSP-α) is a synaptic vesicle protein that prevents activity-dependent neurodegeneration by poorly understood mechanisms. We have studied the synaptic vesicle cycle at the motor nerve terminals of CSP-α knock-out mice expressing the synaptopHluorin transgene. Mutant nerve terminals fail to sustain prolonged release and the number of vesicles available to be released decreases.

Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease.

In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general.

Cysteine string protein-alpha prevents activity-dependent degeneration in GABAergic synapses.

The continuous release of neurotransmitter could be seen to place a persistent burden on presynaptic proteins, one that could compromise nerve terminal function. This supposition and the molecular mechanisms that might protect highly active synapses merit investigation. In hippocampal cultures from knock-out mice lacking the presynaptic cochaperone cysteine string protein-alpha (CSP-alpha), we observe progressive degeneration of highly active synaptotagmin 2 (Syt2)-expressing GABAergic synapses, but surprisingly not of glutamatergic terminals.

Presynaptic dysfunction in Huntington's disease.

HD (Huntington's disease) is produced by the expression of mutant forms of the protein htt (huntingtin) containing a pathologically expanded poly-glutamine repeat. For unknown reasons, in HD patients and HD mouse models, neurons from the striatum and cerebral cortex degenerate and lead to motor dysfunction and dementia. Synaptic transmission in those neurons becomes progressively altered during the course of the disease.