Alteration of intracellular structure and function of glyceraldehyde-3-phosphate dehydrogenase: a common phenotype of neurodegenerative disorders?
Recent evidence reveals that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is not simply a classical glycolytic protein of little interest. Instead, it is a multifunctional protein with diverse cytoplasmic, membrane and nuclear activities. Significantly, each activity is separate and distinctfrom its role in energy production. Its nuclear activities include its emerging role in apoptosis especially in neuronal cells. GAPDH translocates into the nucleus during programmed cell death. Introduction of antisense GAPDH sequences reduces apoptosis and prevents its nuclear translocation. Independent analyses demonstrate that GAPDH may be involved in the cellular phenotype of age-related neurodegenerative disorders. GAPDH binds uniquely in vitro to the beta-amyloid precursor protein (betaAPP), to huntingtin as well as to other triplet repeat neuronal disorder proteins. In Parkinson's disease (PD) cells, immunofluorescent data suggests the co-l localization of GAPDH and alpha-synuclein in Lewy bodies. Drugs used to treat PD bind specifically to GAPDH. Our recent findings (Mazzola and Sirover, 2001) demonstrate a subcellular reduction in GAPDH glycolytic activity in Alzheimer's disease (AD) and in Huntington's disease (HD) cells. The latter may be due to intracellular alteration of GAPDH structure (Mazzola and Sirover 2002). We discuss the hypothesis that the intracellularformation of GAPDH: neuronal protein complexes may represent an emerging cellular phenotype of neurodegenerative disorders. The cytoplasmic binding of neuronal proteins to GAPDH could affect energy production. Nuclear interactions could affect its apoptotic activity. Other functions of this multidimensional protein may also be inhibited. Experimental paradigms to test this hypothesis are considered.
Mazzola
Jennifer L
JL
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Sirover
Michael A
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D013347:Subcellular Fractions / Q000201:enzymology; D018911:Trinucleotide Repeats
D005987:Glyceraldehyde-3-Phosphate Dehydrogenases