Proteostasis and movement disorders: Parkinson's disease and amyotrophic lateral sclerosis.

TitleProteostasis and movement disorders: Parkinson's disease and amyotrophic lateral sclerosis.
Publication TypeJournal Article
Year of Publication2011
AuthorsBosco DA, LaVoie MJ, Petsko GA, Ringe D
JournalCold Spring Harb Perspect Biol
Date Published2011 Oct
Keywordsalpha-Synuclein, Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, HEK293 Cells, Humans, Inclusion Bodies, Mice, Parkinson Disease, Protein Folding, Protein Stability, Protein Transport, Protein-Serine-Threonine Kinases, Proteostasis Deficiencies, RNA-Binding Protein FUS, Superoxide Dismutase, Ubiquitin-Protein Ligases

Parkinson's disease (PD) is a movement disorder that afflicts over one million in the U.S.; amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is less prevalent but also has a high incidence. The two disorders sometimes present together, making a comparative study of interest. Both ALS and PD are neurodegenerative diseases, and are characterized by the presence of intraneuronal inclusions; however, different classes of neurons are affected and the primary protein in the inclusions differs between the diseases, and in some cases is different in distinct forms of the same disease. These observations might suggest that the more general approach of proteostasis pathway alteration would be a powerful one in treating these disorders. Examining results from human genetics and studies in model organisms, as well as from biochemical and biophysical characterization of the proteins involved in both diseases, we find that most instances of PD can be considered as arising from the misfolding, and self-association to a toxic species, of the small neuronal protein α-synuclein, and that proteostasis strategies are likely to be of value for this disorder. For ALS, the situation is much more complex and less clear-cut; the available data are most consistent with a view that ALS may actually be a family of disorders, presenting similarly but arising from distinct and nonoverlapping causes, including mislocalization of some properly folded proteins and derangement of RNA quality control pathways. Applying proteostasis approaches to this disease may require rethinking or broadening the concept of what proteostasis means.

Alternate JournalCold Spring Harb Perspect Biol
PubMed ID21844169
PubMed Central IDPMC3179340