A single gene error of noradrenergic axon growth synchronizes central neurones

One strategy for deciphering inherited neurological disease is to examine the expression of individual genes controlling the assembly and physiology of specific cell groups within the developing mammalian central nervous system (CNS). This neurogenetic approach, using defined single-locus mutations arising on coisogeneic mouse strains, has recently been used to analyse a major class of neuronal membrane diseases involving abnormal excitability, the epilepsies, and to identify examples of hereditary variation in signalling properties at central synapses. An interesting mutation, the Tottering (tg) gene, causes a delayed onset, recessive neurological disorder in the mouse featuring a stereotyped triad of ataxia, intermittent myoclonus and cortical spike-wave discharges accompanied by behavioural absence seizures which resemble petit mal epilepsy. Axon branches of the locus coeruleus, a noradrenergic brain-stem nucleus, hyperinnervate specific target regions of the tg brain. The number of parent coerulean perikarya is unaffected, indicating a true proliferation of the terminal axonal arbor. With the exception of this unusually precise error of axonal growth, no other cytopathology has been identified in the tg brain. Here I present evidence that selective lesions of the central noradrenergic axons early in development limit the expression of the disease.     

Sodium channel density in hypomyelinated brain increased by myelin basic protein gene deletion.

Trophic control over the expression and membrane distribution of voltage-dependent ion channels is one of the principal organizing events underlying the maturation of excitable cells. The myelin sheath is a major structural determinant of regional ion channel topography in central axons, but the exact molecular signals that mediate local interactions between the oligodendrocyte and axolemma are not known. We have found that large caliber fibre pathways in the brain of the mutant mouse shiverer (shi, gene on chromosome 18), whose developmental fate of myelination is averted by deletion of five exons in the myelin basic protein gene, have a striking excess of sodium channels. As cytoplasmic membranes of shiverer oligodendroglia still adhere to axons, the evidence indicates that myelin basic protein or a myelin basic protein-dependent glial transmembrane signal associated with compact myelin formation, rather than a simple glial-axon contact inhibition or an intrinsic genetic program of neuronal differentiation, could be critical in downregulating sodium channel density in axons. Here we use the shiverer mutant to show that mature central nervous system projection neurons with large caliber unmyelinated fibres sustain functional excitability by increasing sodium channel density. This axon plasticity, triggered by the absence of a single glial protein, contributes to the unexpectedly mild degree of neurological impairment in the mutant brain without myelin, and may be a potentially inducible mechanism determining the recovery of function from dysmyelinating disease.     

Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10

Spinocerebellar ataxia type 10 (SCA10; MIM 603516; refs 1,2) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. The gene SCA10 maps to a 3.8-cM interval on human chromosome 22q13-qter (refs 1,2). Because several other SCA subtypes show trinucleotide repeat expansions, we examined microsatellites in this region. We found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of SCA10 in all patients in five Mexican SCA10 families. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset (r2=0.34, P=0.018). Analysis of 562 chromosomes from unaffected individuals of various ethnic origins (including 242 chromosomes from Mexican persons) showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. Our data indicate that the new SCA10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represents the largest microsatellite expansion found so far in the human genome.