Molecular genetic analyses revealed that most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and the polyglutamine diseases share a common molecular pathogenesis, namely protein misfolding and aggregation in the brain. Recently, prion-like transmission of these protein aggregates between cells has been suggested to contribute to the spread of neuropathology. To cope with protein aggregation, organisms have protein quality control systems, consisting of molecular chaperones and protein degradation, and therefore, an imbalance between protein aggregation and these systems would lead to neurodegeneration. Mouse models of neurodegenerative diseases exhibit neurological phenotypes before neuronal death, and these phenotypes are unexpectedly reversible, suggesting that neuronal dysfunction rather than death leads to neurological phenotypes. In addition to dysfunctions inside neurons, dysfunctions of the neuronal and neuro-glial networks also contribute to the pathogenesis in a non-cell autonomous fashion. On the other hand, another class of diseases including several spinocerebellar ataxias has been discovered to be caused by a repeat expansion mutation in untranslated RNA resulting in its accumulation, which is called the RNA repeat diseases. Recent discoveries of RNA-binding protein mutations and a repeat expansion mutation in ALS have highlighted the involvement of abnormal RNA metabolism in its pathogenesis. Recently, various researches on molecular-targeted therapies are in progress, which include high throughput chemical screening, RNAi, and gene therapy, etc. Towards development of a therapy for neurodegenerative diseases, sensitive biomarkers suitable for evaluation of therapeutic efficacy in clinical trials are eagerly anticipated.
