Retire, or 'retire'? I'm sure they could get some mileage out of killing off Ned's wife a second time after he just remarried, but would they really go there?
No, I really can't see that happening.
It certainly brings up questions of precisely what they're going to do now -- best guess is they'll do like they did with Hartman and just not deal with it at all; she's just gone. Which certainly has implications for both Ned and Bart, but I think they can get away with just not acknowledging her -- not mentioning Ned's wife anymore, and focusing school episodes on Bart's relationship with Skinner.
Those dilemmas aside, I believe it's for the best -- I'm still kind of uncomfortable that they recast Lunchlady Doris, even if they only give her about one line every other season. Recasting Latta's roles is a bit more gray area -- IIRC he left the show voluntarily before he died, and it was still early days so his characters weren't so closely identified with him -- but I think it's safe to say that Lunchlady Doris was pretty fucking closely identified with Doris Grau.
Hell, to be frank I've never really liked that they recast Bugs Bunny after Mel Blanc died. (Mel himself purportedly resisted taking over the voice of Elmer Fudd when Arthur Q Bryan passed, but eventually did.)
Frank Oz recently made some comments to the effect that the Muppets should never be played by anyone else but Henson and himself (and the rest of the original cast). I think there's something to that, and certainly they'll never be the same as they were when Jim was alive. On the other hand, I don't doubt for a second that Jim would have wanted those characters to survive him and continue to bring joy to generations of kids of all ages.
It's really a case-by-case basis, I suppose. Some characters are bigger than the writers, artists, actors, puppeteers, etc. associated with them, some are open to a myriad of interpretations -- hell, I've got an entire FF6 party named after actors who've played Batman -- and some are so closely and fundamentally tied to a single voice that they shouldn't be given to anybody else. I think most everybody on The Simpsons falls into the latter category.
It's morbid to consider, but it's bound to come up: this is one more reason it's worth considering that Simpsons should start winding down. Most of the principals are in their fifties, but Shearer's almost 70. I want the show to end before any of the leads die. As it stands, losing Wallace is heartbreaking -- not as heartbreaking as losing Hartman was (and I still think it's very much worth noting that the era everyone pegs as the show's downturn coincides with his death), but it's one more absence that can never be filled and will never be forgotten.
25 years would be a pretty good round number to end on, but if this were going to be the last season we'd have heard about it by now.