Disease relevance of Tbce

• The first manifestations of progressive motor neuronopathy in homozygous pmn/pmn mice become apparent in the hind limbs at the end of the third post-natal week, and all the mice die up to 6 or 7 weeks after birth from respiratory paralysis [1].
• To assess its therapeutic potential in treating neurodegenerative diseases such as amyotrophic lateral sclerosis, we treated mutant mice displaying motoneuron degeneration (progressive motor neuropathy; pmn) with encapsulated GDNF-secreting cells [2].
• Therefore, despite its potential in rescuing motoneuron cell bodies, the inability of GDNF to prevent nerve degeneration in pmn/pmn mice suggests that its usefulness in the treatment of motor neuron diseases may be restricted to cotreatment with other factors that act on the nerve process [2].
• In vivo, several compounds have been shown to possess neural rescue properties in models of unilateral hypoxia/ischaemia, focal ischaemia, facial nerve axotomy, pmn mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and MPTP non-human primate [3].

High impact information on Tbce

• A missense mutation in Tbce causes progressive motor neuronopathy in mice [4].
• Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice [4].
• We demonstrate here that adenovirus-mediated gene transfer of neurotrophin-3 (NT-3) can produce substantial therapeutic effects in the mouse mutant pmn (progressive motor neuronopathy) [5].
• Here we report that CNTF greatly reduces all the functional and morphological changes in pmn/pmn mice, an autosomal recessive mutant leading to progressive caudo-cranial motor neuron degeneration [1].
• We localized the genetic defect in pmn mice to a missense mutation in the tubulin-specific chaperone E (Tbce) gene on mouse chromosome 13 [6].

Biological context of Tbce

• Quantitative analysis of leukemia inhibitory factor (LIF) mRNA expression revealed that the dramatic upregulation seen in wild-type mice after peripheral nerve lesion did not occur in pmn mice [7].
• Since Bcl-2 acts strictly on neuronal cell body survival without compensating for nerve degeneration in pmn/pmn/bcl-2 mice, this proto-oncogene would not in itself be sufficient for treatment of neurodegenerative diseases where axonal impairment is a major component [8].
• In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2-4], transgenic expression of the anti-apoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor [6] prevents the apoptosis of the motoneuron soma; however, they were unable to affect the life span of the animals [9].

Anatomical context of Tbce

• Facial nerve lesion dramatically increased the number of surviving motoneurons in pmn mice [7].
• To evaluate whether endogenous CNTF, released after nerve injury from the cytosol of Schwann cells, supports motoneuron survival, we transected the facial nerve in 4-week-old pmn mice [7].
• Using ELISA and RT-PCR analyses in muscle, spinal cord and serum of AdNT-3-treated pmn mice, we have investigated the contribution of these processes to the observed therapeutic effects [10].
• Adenovirus-mediated transfer of the neurotrophin-3 gene into skeletal muscle of pmn mice: therapeutic effects and mechanisms of action [10].
• A murine model of motoneuron disease, the pmn/pmn mouse, shows a reduction in the retrograde transport of fluorescent probes applied directly onto the cut end of sciatic nerve [11].

Associations of Tbce with chemical compounds

• Four new isomeric azine-bridged complexes ([(cis-Pt(NH(3))(2)Cl)(2)(mu-pzn)]Cl(2) (1a) (pzn = pyrazine) and its corresponding nitrate salt (1b), [(cis-Pt(NH(3))(2)Cl)(2)(mu-pmn)]Cl(2) (2) (pmn = pyrimidine), and [(cis-Pt(NH(3))(2)Cl)(2)(mu-pdn)](NO(3))(2) (3) (pdn = pyridazine) have been newly synthesized as potential anticancer compounds [12].
• Transgenic mice overexpressing an axonally secreted inhibitor of serine proteases (neuroserpin) were crossed with mice characterized by a "dying-back" motor neuron disease [progressive motor neuronopathy (pmn/pmn)] [13].

Other interactions of Tbce

• This protective effect was absent in pmn mice lacking endogenous CNTF [7].
• We examined the effects of Bcl-2 overexpression in a genetic mouse model with motor neuron disease (progressive motor neuronopathy/pmn) [8].
• For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ("slow Wallerian degeneration") mutation, which slows axon degeneration and synapse loss [7-9] [9].
• Increased accumulation of transferrin by motor neurons of the mouse mutant progressive motor neuronopathy (pmn/pmn) [14].

Analytical, diagnostic and therapeutic context of Tbce

• After intramuscular injection of the NT-3 adenoviral vector, pmn mice showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function as assessed by electromyography [5].

References