Untangling huntingtin’s mysteries
We have reached a critical juncture in the search for a cure for Huntington disease (HD), and nowhere was this more apparent than in Boston recently at the annual research conference sponsored by the Hereditary Disease Foundation (HDF, http://www.hdfoundation.org), Huntington Disease 2000: Changes, Advances and Good News (CAG). The symposium provided a forum for the expanding community of Huntington researchers to share their latest results.
ICE, neuronal apoptosis and neurodegeneration
Significant progress has recently occurred in the understanding of the molecular mechanisms mediating vertebrate programmed cell death, or apoptosis. New advances in this field have stemmed from the identification of ICE (caspase-1) as the founding member of the mammalian caspase cell death family.
Hunting down Huntington’s disease
Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis
Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1G93A mice.
Huntingtin inhibits caspase‐3 activation
Huntington’s disease results from a mutation in the HD gene encoding for the protein huntingtin. The function of huntingtin, although beginning to be elucidated, remains largely unclear.
Caspases in Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominant condition, resulting from a mutation in huntingtin (htt). Htt is a novel protein, and its normal function is at present not well understood. Nuclear translocation of mutant htt in vitro up-regulates expression of the cell death gene caspase-1.
Inhibitors of Cytochrome c Release with Therapeutic Potential for Huntington’s Disease
Release of mitochondrial cytochrome c resulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochrome c release has not been demonstrated in Huntington’s disease (HD).
Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington’s disease
Caspases play an important role in neurodegeneration in Huntington’s disease (HD). Members of the Bcl-2 family are critical modulators of terminal cell death pathways. However, alterations of Bcl-2 family members and their functional role in an in vivo model of HD have not been documented.
Melatonin Deficits Result in Pathologic Metabolic Reprogramming in Differentiated Neurons
Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production.
Dysregulation of Receptor Interacting Protein-2 and Caspase Recruitment Domain Only Protein Mediates Aberrant Caspase-1 Activation in Huntington’s Disease
Caspase-1 plays a role in the pathogenesis of a variety of neurological diseases. Caspase-1 activation is an early event in models of Huntington’s disease (HD). However, mechanisms regulating the activation of this apical caspase in cell death are not known. Receptor interacting protein-2 (Rip2) and caspase recruitment domain (CARD) only protein (Cop) are two CARD proteins with significant homology to the caspase-1 CARD and modulate caspase-1 activation in inflammation.