Protease inhibitors suppress the degradation of mutant adrenoleukodystrophy proteins but do not correct impairment of very long chain fatty acid metabolism in adrenoleukodystrophy fibroblasts.

The adrenoleukodystrophy (ALD) gene product, ALD protein (ALDP), was not detected in fibroblasts from our or most other patients with ALD as determined by immunoblot or immunocytochemistry. We investigated the stability of mutant ALDP and found from pulse-chase experiments that the respective half-lives of the normal and mutant #140 (Gly512Ser) and #249 (Arg660Trp) were 72.6, 32.1 and 26.1 min, indicative that mutant ALDPs are less stable than normal ones. The mutant ALDPs were detectable in fibroblasts cultured with the protease inhibitor E-64 or leupeptin. Protease inhibitor treatment for 2 to 28 days did not affect the amount of very long chain fatty acid (VLCFA), C26:0, or VLCFA beta-oxidation activity in ALD fibroblasts. Protease inhibitors therefore suppress the degradation of ALDP but do not correct the impairment of VLCFA metabolism in ALD.