6 October 2002. Protein aggregation is a hallmark of many neurodegenerative diseases. In certain cases, including Parkinson’s disease, these aggregates include ubiquitin, a proteinaceous tag that earmarks proteins for degradation. Researchers from the National Cancer Institute, Frederick, Maryland, report in Nature Genetics online that the identification of a mutation in mice that causes ataxia, or muscle paralysis. Interestingly, this mutation, an insertion of 5.2 kb of DNA, occurs in the gene for ubiquitin-specific protease 14 (Usp14).
First author Scott Wilson, working under the direction of Nancy Jenkins at NCI, together with co-workers at Northwestern University, Chicago, and the Novartis Foundation, San Diego, California, mapped the mutation, which arose spontaneously in laboratory mice, to a small section of chromosome 18. Close examination of the genes in that region showed that the insertion, which causes hind limb paralysis and early death, creates premature stop codons in Usp14 transcripts, resulting in a dramatic loss of expression.
The precise neurological role of Usp14 is unclear. At the cellular level homozygous mutant mice (axJ/axJ) show no detectable neurological lesions, ubiquitin-containing aggregates, or loss of neurons. However, the authors did find that synaptic transmission at the neuromuscular junctions of these animals was severely impaired; the spontaneous currents between the nerve and the muscle, or miniature end-plate currents, were lower in frequency and higher in amplitude than in normal mice. By measuring spontaneous end-plate currents, and those elicited by stimuli, Wilson et al. discovered that axJ/axJ mice had a 50 percent loss in transmission across the neuromuscular junction. The CNS also seems to be affected by this mutation as indicated by loss of paired-pulse facilitation (PPF), the heightened response of a nerve to a second stimulus closely following a first. PPF is a measure of synaptic plasticity, or the ability of neurons to make and break synapses, and loss of this type of facilitation correlates with learning impairment.
Overall the data indicates some role for Usp14 in synaptic function, a role that may equate to that played by the gene fat facets, recently found in Drosophila (see DiAntonio et al., Nature). However, the relationship between the protease and the ubiquitin-associated neurodegenerative diseases is hard to make, though the authors do suggest that Usp14 mutations may contribute to other disorders linked to altered synaptic function, namely major affect disorder 1 and schizophrenia disorder 8, both associated with genes that map near Usp14.-Tom Fagan
Wilson SM, Bhattacharyya B, Rachel RA, Coppola V, Tessarollo L, Householder DB, Fletcher CF, Miller RJ, Copeland NG, Jenkins N. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nature Genetics Advance online publication 2002 October 7. Abstract