Alternatively, intracellular sequestration of mutant heterotrimers could lead to extracellular deficiency of α1α1α2 heterotrimers.
Because CaM regulates many other Ca2+ channel subtypes, including those that predominate in neurons, these mutant CaMs could lead to a multi-system disorder similar to TS.
Although the ldh and pfl double mutant strain could lead to an improved succinate production to about 28.2 g/L, this strain lost its ability to ferment glucose anaerobically due to redox imbalance [ 33].
Either deficiency of normal heterotrimers or presence of mutant heterotrimers could lead to compromised basement membranes that perturb cell matrix signaling via cell surface receptors or growth factor-mediated cell cell signaling.
Indeed, reduced striatal TrkB expression has been reported in knockin HD cellular and mouse models, exon-1 HD transgenic mice and HD human brain, which suggests that mutant huntingtin could lead to reduced neurotrophic support not only by altering BDNF levels but also by affecting TrkB expression.
Although we cannot exclude other mechanisms in SOD1-linked familial ALS, the one proposed here has the strength of explaining how a large and diverse set of SOD1 mutant proteins all could lead to disease through the same mechanism.
Since the S503 residue of AAV-DJ was equivalent to the S501 residue of AAV2, which turn out to be an effective phosphorylation site of AAV2, it remains to be further studied if the S501A mutant of AAV2 could lead to significant enhancement in AAV2-mediated gene delivery.
Large changes in the percentage level of mutated mtDNA are observed in small human pedigrees transmitting heteroplasmic mtDNA mutations (Chinnery et al., 2000), and so even low levels of mutant mtDNA carry-over could lead to maternal descendants with high mutation levels, causing severe multi-system disease (DiMauro and Schon, 2003).
In this brief review, we explore some of the possible mechanisms that could underlie this poorly understood phenomenon, with the expectation that an understanding of the cause of dwarfing in lignin biosynthetic mutants and transgenic plants could lead to new strategies for the development of improved bioenergy feedstocks.
It remains to be further investigated if multiple mutants of AAV-DJ could lead to enhancement in in vitro gene delivery.
