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 beta-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.