Perturbed Signal Transduction in Neurodegenerative Disorders Involving Aberrant Protein Aggregation

Mark P. Mattson, Michael Sherman

Research output: Contribution to journalArticle

Abstract

Aggregation of abnormal proteins, both inside and outside of cells, is a prominent feature of major neurodegenerative disorders, including Alzheimer's, Parkinson's, polyglutamine expansion, and prion diseases. Other articles in this special issue of NeuroMolecular Medicine describe the genetic and molecular factors that promote aberrant protein aggregation. In the present article, we consider how it is that pathogenic aggregation-prone proteins compromise signal transduction pathways that regulate neuronal plasticity and survival. In some cases the protein in question may have widespread and relatively nonspecific effects on signaling. For example, amyloid β-peptide induces membrane-associated oxidative stress, which impairs the function of various receptors, ion channels and transporters, as well as downstream kinases and transcription factors. Other proteins, such as polyglutamine repeat proteins, may affect specific protein-protein interactions, including those involved in signaling pathways activated by neurotransmitters, neurotrophins, and steroid hormones. Synapses are particularly sensitive to abnormal protein aggregation and impaired synaptic signaling may trigger apoptosis and related cell death cascades. Impairment of signal transduction in protein aggregation disorders may be amenable to therapy as demonstrated by a recent study showing that dietary restriction can preserve synaptic function and protect neurons in a mouse model of Huntington's disease. Finally, emerging findings are revealing how activation of certain signaling pathways can suppress protein aggregation and/or the cytotoxicity resulting from the abnormal protein aggregation. A better understanding of how abnormal protein aggregation occurs and how it affects and is affected by specific signal transduction pathways, is leading to novel approaches for preventing and treating neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)109-131
Number of pages23
JournalNeuroMolecular Medicine
Volume4
Issue number1-2
DOIs
StatePublished - 2003

Fingerprint

Neurodegenerative Diseases
Signal Transduction
Proteins
Prion Diseases
Neuronal Plasticity
Huntington Disease
Nerve Growth Factors
Ion Channels
Amyloid
Synapses
Neurotransmitter Agents
Molecular Biology
Oxidative Stress
Cell Death
Transcription Factors
Phosphotransferases
Steroids
Medicine
Hormones
Apoptosis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Perturbed Signal Transduction in Neurodegenerative Disorders Involving Aberrant Protein Aggregation. / Mattson, Mark P.; Sherman, Michael.

In: NeuroMolecular Medicine, Vol. 4, No. 1-2, 2003, p. 109-131.

Research output: Contribution to journalArticle

Mattson, Mark P. ; Sherman, Michael. / Perturbed Signal Transduction in Neurodegenerative Disorders Involving Aberrant Protein Aggregation. In: NeuroMolecular Medicine. 2003 ; Vol. 4, No. 1-2. pp. 109-131.
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