Neuropathology in Drosophila Membrane Excitability Mutants

Abstract

Mutations affecting ion channels and neuronal membrane excitability have been identified in Drosophila as well as in other organisms and characterized for their acute effects on behavior and neuronal function. However, the long-term effect of these perturbations on the maintenance of neuronal viability has not been studied in detail. Here we perform an initial survey of mutations affecting Na 1 channels and K 1 channels in Drosophila to investigate their effects on life span and neuronal viability as a function of age. We find that mutations that decrease membrane excitability as well as those that increase excitability can trigger neurodegeneration to varying degrees. Results of double-mutant interactions with dominant Na 1 /K 1 ATPase mutations, which themselves cause severe neurodegeneration, suggest that excitotoxicity owing to hyperexcitability is insufficient to explain the resultant phenotype. Although the exact mechanisms remain unclear, our results suggest that there is an important link between maintenance of proper neuronal signaling and maintenance of long-term neuronal viability. Disruption of these signaling mechanisms in any of a variety of ways increases the incidence of neurodegeneration.

Acquired temperature‐sensitive paralysis as a biomarker of declining neuronal function in aging Drosophila

“…3a-c). This is consistent with the findings that Fergestad et al, 2006). Paralysis in mle napts flies can be completely rescued by the addition of a single extra copy of the para + gene (Stern et al, 1990).…”

“…The notion that sensitivity to ts paralysis reflects the level of neuronal function in flies is supported by the fact that extensive screens for ts paralytic phenotype have recovered a number of mutations in genes associated with neuronal function. Mutation in such genes is often associated with shorter lifespan and neurodegeneration (Fergestad et al, 2006). In addition, we propose that ts paralysis could be used as a biomarker of increased frailty and decline of neuronal function during aging in Drosophila.…”

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

“…Life-span analysis: Life spans were measured at 29°accord-ing to standard protocols as described previously (Kretzschmar et al 1997;Lin et al 1998;Min and Benzer 1999;Palladino et al 2002;Palladino et al 2003;Fergestad et al 2006b). In brief, newly eclosed animals were collected, separated by sex, placed in vials (up to 20 per vial), and transferred to fresh vials daily, and survivorship was recorded for each vial.…”

“…20 for each genotype). Neurodegeneration for each genotype was scored as previously described (Fergestad et al 2006b). Briefly, each genotype was assigned a score from 0 to 5 on the basis of the frequency and severity of vacuolar pathology observed in brain serial sections as follows.…”

wasted away , a Drosophila mutation in triosephosphate isomerase, causes paralysis, neurodegeneration, and early death

“…Indeed, an initial histological survey of our collection demonstrated that it was enriched for mutants with defects in neuronal survival: Ϸ10% of the mutants examined manifest varying degrees of age-dependent neuropathology in the central nervous system (17). Among the previously identified mutants associated with neurodegeneration are those encoding ion channels, the Na ϩ ͞K ϩ ATPase, and components of the synaptic release machinery (17)(18)(19).…”