Possible chemical initiators of cognitive dysfunction in phenylketonuria, Parkinson's disease and Alzheimer's disease.
Though a great deal is known of the pathophysiology of phenylketonuria (PKU), Parkinson's disease (PD) and Alzheimer's disease (AD) very little is known regarding possible chemical species responsible for initiating the cascade of events that ultimately cause cognitive dysfunction. Can these be viewed as inborn errors in metabolism, occurring at various stages in the life cycle, analogous to adult onset diabetes? One major deficiency in understanding such conditions is the paucity of information regarding the total metabolic pathway for various amino acids that may be implicated in their causation. For example in PKU, its etiology was reported in 1934 and dietary restriction of phenylalanine proved effective for individuals with unsatisfactory metabolism of phenylalanine. Yet, current phenylalanine metabolism does not take into account fully the multiple biochemical pathways operating whose role is preventing burdensome accumulations of intermediates that can contribute to morbidity and toxicity. The same may apply for metabolism of tyrosine in PD and methionine in AD. Especially important, are the presence of labile and reactive chemical species which may be causative agents in protein alteration, misfolding and the creation of prions in neurodegenerative diseases, thereby preventing normal protein catabolism and excretion. Though genetic or epigenetic factors must be responsible, the question remains how are these translated into the chemical structures responsible for disease initiation? The purpose of this presentation is to explore potential labile metabolites in those biochemical pathways, which may be contributing factors. Finally it is worth noting, that drug development has been increasingly designed based upon targeting genetic deficiencies. The effectiveness of this approach for the treatment of these neurodegenerative illnesses will be determined in the future.
Emeritus of the College of Pharmacy of The Ohio State University, United States. Electronic address: al1953barb@aol.com.
Albert H
AH
Soloway
Paul D
PD
Soloway
Victor D
VD
Warner
D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism*; D002396:Catechols / Q000737:chemistry / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology*; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008715:Methionine / Q000737:chemistry / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000150:complications / Q000378:metabolism*; D010649:Phenylalanine / Q000737:chemistry / Q000378:metabolism; D010661:Phenylketonurias / Q000150:complications / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
D002396:Catechols; D014443:Tyrosine; D010649:Phenylalanine; D008715:Methionine; C034221:catechol