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Aging and disease    2017, Vol. 8 Issue (3) : 334-345     DOI: 10.14336/AD.2016.1030
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On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine
Hipkiss Alan R.*
Aston Research Centre for Healthy Ageing (ARCHA), School of Health and Life Sciences, Aston University, Birmingham B4 7ET, United Kingdom.
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Abstract  

Recent research shows that energy metabolism can strongly influence proteostasis and thereby affect onset of aging and related disease such as Parkinson’s disease (PD). Changes in glycolytic and proteolytic activities (influenced by diet and development) are suggested to synergistically create a self-reinforcing deleterious cycle via enhanced formation of triose phosphates (dihydroxyacetone-phosphate and glyceraldehyde-3-phosphate) and their decomposition product methylglyoxal (MG). It is proposed that triose phosphates and/or MG contribute to the development of PD and its attendant pathophysiological symptoms. MG can induce many of the macromolecular modifications (e.g. protein glycation) which characterise the aged-phenotype. MG can also react with dopamine to generate a salsolinol-like product, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinaline (ADTIQ), which accumulates in the Parkinson’s disease (PD) brain and whose effects on mitochondria, analogous to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), closely resemble changes associated with PD. MG can directly damage the intracellular proteolytic apparatus and modify proteins into non-degradable (cross-linked) forms. It is suggested that increased endogenous MG formation may result from either, or both, enhanced glycolytic activity and decreased proteolytic activity and contribute to the macromolecular changes associated with PD. Carnosine, a naturally-occurring dipeptide, may ameliorate MG-induced effects due, in part, to its carbonyl-scavenging activity. The possibility that ingestion of highly glycated proteins could also contribute to age-related brain dysfunction is briefly discussed.

Keywords Parkinson’s      methylglyoxal      glycolysis      mitochondria      proteolysis      glycation      homeostasis      carnosine      aging     
Corresponding Authors: Hipkiss Alan R.   
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These authors contributed equally to the work.

Issue Date: 01 June 2017
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Hipkiss Alan R.. On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine[J]. Aging and disease, 2017, 8(3): 334-345.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2016.1030     OR     http://www.aginganddisease.org/EN/Y2017/V8/I3/334
Possible common causal factors or processes to Parkinson’s disease and aging
Endogenous synthesis of methylglyoxal (MG): possible causes
  Excessive glycolysis
  High glycemic index diet
  Inactivation of triose-phosphate isomerase
  Decline of MG-scavenging or MG-eliminating processes
Effects of MG include
  Mitochondrial dysfunction
  Proteostastic dysfunction
  Protein cross-linking
  Protein AGEs
  Formation of ADTIQ (neurotoxin)
Increased intake and possible effects of dietary protein-AGEs
  Reaction with RAGEs in gut wall
  Cell to cell transmission to CNS (??)
  Induction of cognitive dysfunction (??)
Possible ameliorative strategies towards aging and PD
  Decreased glycolysis
  Increased mitochondrial function
  Low glycemic index diet
  Increased intake or synthesis of carnosine (an anti-glycating/MG-scavenging agent).
  Increased intake of leafy plant tissues containing anti-glycating/MG scavenging agents.
   Raised glyoxalase activity.
Table 1  Summary of factors which may either provoke or ameliorate age-related changes which contribute to Parkinson’s disease onset
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