Neurogenetics: insights into degenerative diseases and approaches to schizophrenia

The etiology and pathogenesis of neurodegenerative disorders has been greatly advanced by the discovery of mutations that cause Mendelian forms of these disorders. For instance, the CAG repeat expansion diseases have provided the opportunity to clarify the genotype-phenotype relationship in an entire group of disorders. Understanding of Alzheimer's disease pathogenesis has been greatly advanced by the appreciation that APP or presenilin mutations, duplication of APP in trisomy 21, and the ApoE4 allele may all function to increase accumulation of the toxic A-beta peptide. Similarly, interactions among the protein products of the genes implicated in rare Mendelian forms of Parkinson's disease suggest pathogenic pathways of potential relevance to the common sporadic forms of PD. Most cases of schizophrenia appear to arise from a combination of genetic and environmental factors, each making a small contribution to the phenotype, but identifying these factors has proven difficult. However, as in AD and PD, rare pedigrees exist in which major mental illness appears to be inherited in a Mendelian fashion, including two pedigrees in which schizophrenia or affective disorder is associated with mutations in DISC1. Determining the cellular localization, protein partners, and function of the normal and mutated DISC1 protein may provide important insights into the more common forms of major mental illness. Thus the same approaches that have been successful for understanding neurodegenerative diseases may help elucidate the etiology and pathogenesis of schizophrenia and other psychiatric disorders.