Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases

Catherine M. Cahill, Debomoy Lahiri, Xudong Huang, Jack T. Rogers

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Recent studies that alleles in the hemochromatosis gene may accelerate the onset of Alzheimer's disease by five years have validated interest in the model in which metals (particularly iron) accelerate disease course. Biochemical and biophysical measurements demonstrated the presence of elevated levels of neurotoxic copper zinc and iron in the brains of AD patients. Intracellular levels of APP holoprotein were shown to be modulated by iron by a mechanism that is similar to the translation control of the ferritin L- and H mRNAs by iron-responsive element (IRE) RNA stem loops in their 5′ untranslated regions (5′UTRs). More recently a putative IRE-like sequence was hypothesized present in the Parkinsons's alpha synuclein (ASYN) transcript (see [A.L. Friedlich, R.E. Tanzi, J.T. Rogers, The 5'-untranslated region of Parkinson's disease alpha-synuclein messenger RNA contains a predicted iron responsive element, Mol. Psychiatry 12 (2007) 222-223. [6]]). Together with the demonstration of metal dependent translation of APP mRNA, the involvement of metals in the plaque of AD patients and of increased iron in striatal neurons in the substantia nigra (SN) of Parkinson's disease patients have stimulated the development of metal attenuating agents and iron chelators as a major new therapeutic strategy for the treatment of these neurodegenerative diseases. In the case of AD, metal based therapeutics may ultimately prove more cost effective than the use of an amyloid vaccine as the preferred anti-amyloid therapeutic strategy to ameliorate the cognitive decline of AD patients.

Original languageEnglish
Pages (from-to)615-628
Number of pages14
JournalBiochimica et Biophysica Acta - General Subjects
Volume1790
Issue number7
DOIs
StatePublished - Jul 2009

Fingerprint

Neurodegenerative diseases
alpha-Synuclein
Amyloid beta-Protein Precursor
Neurodegenerative Diseases
Iron
Inflammation
Metals
Apoferritins
5' Untranslated Regions
Amyloid
Messenger RNA
Parkinson Disease
Corpus Striatum
Hemochromatosis
Protein Biosynthesis
Substantia Nigra
Therapeutics
Chelating Agents
Neurons
Psychiatry

Keywords

  • ATP
  • Hippocampus
  • Ketogenic diet
  • Mitochondria
  • Succinic semialdehyde dehydrogenase deficiency

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases. / Cahill, Catherine M.; Lahiri, Debomoy; Huang, Xudong; Rogers, Jack T.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1790, No. 7, 07.2009, p. 615-628.

Research output: Contribution to journalArticle

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