The cell biology of alpha-synuclein: a sticky problem?
Parkinson's disease (PD) is the most common neurodegenerative motor disorder, marked by chronic progressive loss of neurons in the substantia nigra, thereby damaging purposeful control of movement. For decades, it was believed that PD was caused solely by environmental causes. However, the discovery of genetic factors involved in PD has revolutionized our attempts to understand the disease's pathology. PD now appears to be more polygenetic than previously thought and is most likely caused by a complex interaction of genetic risks and environmental exposures. The first gene found to be mutated in PD encodes for the presynaptic protein alpha-synuclein, which is also a major component of Lewy bodies and Lewy neurites, the neuropathological hallmarks of the disease. While these findings provide a classic example of how rare genetic mutations in disease can point to important pathways in idiopathic disease pathologies, much of the study of alpha-synuclein has focused on understanding how this protein undergoes the transition from an unfolded monomer to amorphous aggregates or Lewy body-like filaments rather than addressing what its fundamental function might be. Since alterations in synuclein function may predispose to the disease pathology of PD, regardless of the presence of genetic mutations, a more thorough understanding of the cellular regulation and function of alpha-synuclein may be of crucial importance to our understanding of this degenerating disorder.
Cole
Nelson B
NB
National Human Genome Research Institute (NHGRI), Bethesda, MD 20892, USA. ncole@nhgri.nih.gov
Murphy
Diane D
DD
D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000503:physiopathology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010750:Phosphoproteins / Q000502:physiology*; D011487:Protein Conformation; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein