Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH

Abstract

At least five adult-onset neurodegenerative diseases, including Huntingtin disease (HD), and dentatorubral-pallidoluysian atrophy (DRPLA) are produced by genes containing a variably increased CAG repeat within the coding region. The size range of the repeats is similar in all diseases; unaffected individuals have fewer than 30 CAG repeats, whereas affected patients usually have more than 40 repeats. The size of the inherited CAG repeat correlates with the severity and age of disease onset. The CAG triplet repeat produces a polyglutamine domain in the expressed proteins. All of these diseases are inherited in a dominant fashion, and a pathologic gain of function in gene carriers has been proposed. We sought to identify proteins in the brain that selectively interact with polyglutamine-domain proteins, hypothesizing that the polyglutamine domain may determine protein-protein interactions.

Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death

“…GAPDH binds to glutamine repeats in Huntingtin and other polyglutaminecontaining proteins associated with neurodegenerative diseases (16,17). GAPDH also binds to amyloid precursor protein (18).…”

“…Moreover, GAPDH can bind to Huntingtin, the protein whose glutamine repeats may mediate the symptoms of Huntington disease (HD) (16), as well as to the gene products with glutamine repeats involved in other neurodegenerative diseases such as spinocerebellar ataxia type-I (17), spinobulbar muscular atrophy (17), and dentatorubral pallidoluysian atrophy (16). Furthermore, GAPDH can bind to the cytoplasmic domain of amyloid precursor protein (18).…”

Imaging in cell-based therapy for neurodegenerative diseases

“…Nevertheless, recent studies have suggested that abnormal interactions between the mutated huntingtin and other proteins could be involved in the pathogenesis of HD. Thus, huntingtin has been shown to interact with several proteins including a cytoplasmic protein that associates with microtubules, mitochondria, and synaptic vesicles (HAP-1; [45]), glyceraldehyde phosphate dehydrogenase (GAPDH; [46]), an unidentified calmodulin associated protein [47], an ubiquitin-associated protein (HIP-2; [48]), and a protein homologous to the yeast cytoskeleton-associated protein sla2p (HIP-1; [49]). …”

Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

“…To date, a number of hypotheses regarding the molecular mechanisms of neurodegeneration caused by expansion of CAG repeats have been proposed, including position effect hypothesis, polar zipper theory, a hypothesis of the expanded polyglutamine tracts as a substrate for transglutaminase, and a hypothesis of neurotoxicity caused by the expanded polyglutamine tracts. Recently proteins which may interact with the polyglutamine tract were identified (HAP1 and GAPDH) (Li et al, 1995;Burke et al, 1996). Burke et al proposed that stronger binding of mutant DRPLAP carrying expanded polyglutamine tract with GAPDH than that of wild type DRPLAP may result in a decrease in GAPDH activity and energy failure in cells expressing mutant DRPLAP (Burke et al, 1996).…”

“…Recently proteins which may interact with the polyglutamine tract were identified (HAP1 and GAPDH) (Li et al, 1995;Burke et al, 1996). Burke et al proposed that stronger binding of mutant DRPLAP carrying expanded polyglutamine tract with GAPDH than that of wild type DRPLAP may result in a decrease in GAPDH activity and energy failure in cells expressing mutant DRPLAP (Burke et al, 1996).…”