Recently researchers have found that deposits do not correlate with cell death. Now Fusco et al. have found in detail that the localization of huntingtin does not correlate with cell death. The inescapable conclusion is that mutant huntingtin does not directly kill brain cells.
Mutant huntingtin as Areanas et al found does cause a systemic metabolic defect. It is clear that it is the decrease of ATP that kills cells. In support of this is the fact ischemia kills the same population of brain cells as killed in HD. Why some brain structures are more sensitive to ATP decrease (by 3NPA) can be answered with out consideration of mutant huntingtin.
For some time it has been suggested, from HD databases, that HD has two mechanisms, one to only initiate the other. Perhaps it is an immune cascade that kills cells independent of mutant huntingtin. This fascinating story continues to unfold. Jerry 01/10/99
J Neurosci 1999 Feb 15;19(4):1189-1202, Fusco FR, et al.
Immunohistochemistry and single-cell RT-PCR were used to characterize the localization of huntingtin and/or its mRNA in the major types of striatal neurons and in corticostriatal projection neurons in rats. Single-label immunohistochemical studies revealed that striatum contains scattered large neurons rich in huntingtin and more numerous medium-sized neurons moderate in huntingtin.
Double-label immunohistochemical studies showed that the large huntingtin-rich striatal neurons include nearly all cholinergic interneurons and some parvalbuminergic interneurons. Somatostatinergic striatal interneurons, which are medium in size, rarely contained huntingtin.
Calbindin immunolabeling showed that the vast majority of the medium-sized striatal neurons that contain huntingtin are projection neurons, but only ~65% of calbindin-labeled projection neurons (localized to the matrix compartment of striatum) were labeled for huntingtin. Calbindin-containing projection neurons of the matrix compartment and calbindin-negative projection neurons of the striatal patch compartment contained huntingtin with comparable frequency.
Single-cell RT-PCR confirmed that striatal cholinergic interneurons contain huntingtin, but only ~65% of projection neurons contained detectable huntingtin message. The finding that huntingtin is not consistently found in striatal projection neurons [which die in Huntington's disease (HD)] but is abundant in striatal cholinergic interneurons (which survive in Huntington's disease) suggests that the mutation in huntingtin that causes HD may not directly kill neurons. In contrast to the heterogeneous expression of huntingtin in the different striatal neuron types, we found all corticostriatal neurons to be rich in huntingtin protein and mRNA.
One possibility raised by our findings is that the HD mutation may render corticostriatal neurons destructive rather than render striatal neurons vulnerable.