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.