alpha-synuclein and Friedreich-Ataxia

Linkage of the Huntington's disease gene to chromosome 4 in 1983 marked the birth of modern genetics in movement disorders. The discovery that an expanded trinucleotide DNA repeat was central to the mechanism of this disease has been repeated over and over in a growing list of inherited ataxias. In 1997, a different mutation and genetic mechanism was discovered in a severe type of generalized primary torsion dystonia - Oppenheim's dystonia. Before this, only the genetic cause for rare metabolic dystonias was known, notably dopa-responsive (Segawa's) dystonia. In the same year, from the identification of mutation in the alpha-synuclein gene in rare pedigrees with autosomal dominant parkinsonism, arose the concept that Parkinson's disease may be part of a broader group of 'synucleinopathies', in which there is a fundamental defect in protein processing. In the following year, mutations in autosomal recessive juvenile onset parkinsonism were found in a gene called 'parkin'. Parkin mutations are a more common cause of parkinsonism than the rare alpha-synuclein mutations, particularly in young-onset disease. However, a most important understanding, occurring in the last year, has been the relationship between the parkin gene product, alpha-synuclein and abnormal protein degradation in the cell. A unified theory of neuronal death in Parkinson's disease is emerging, pointing to potential new therapies in the future.

Topics: alpha-Synuclein; Carrier Proteins; Chromosome Mapping; Chromosomes, Human; Dystonic Disorders; Friedreich Ataxia; Genes, Dominant; Genes, Recessive; Humans; Huntingtin Protein; Huntington Disease; Ligases; Minisatellite Repeats; Molecular Chaperones; Movement Disorders; Nerve Tissue Proteins; Nuclear Proteins; Parkinson Disease; Spinocerebellar Ataxias; Synucleins; Ubiquitin-Protein Ligases