Properties of NACP/alpha-synuclein and its role in Alzheimer's disease.
The precursor of the non-amyloid beta/A4 protein (non-Abeta) component of Alzheimer's disease amyloid (NACP)/alpha-synuclein is the human homologue of alpha-synuclein, a member of a protein family which includes alpha-, beta- and gamma-synuclein. This protein is thought to be involved in neuronal plasticity because of its unique expression, mainly in the telencephalon during maturation. Consequently, disarrangement of NACP/alpha-synuclein might disrupt synaptic activity, resulting in memory disturbance. Previous studies have shown that damage to synaptic terminals is closely associated with global cognitive impairment and is an early event in the pathogenesis of Alzheimer's disease. Although the relationship between synaptic damage and amyloidogenesis is not clear, some proteins at the synaptic site have been implicated in both neuronal alteration and amyloid formation. Indeed, abnormal accumulation of both NACP/alpha-synuclein and Abeta precursor protein occurs at synapses of Alzheimer's patients. Other evidence suggests that NACP/alpha-synuclein is a component of the Lewy bodies found in patients with Parkinson's disease or dementia with Lewy bodies, and that a point mutation in this protein may be the cause of familial Parkinson's disease. Consequently, abnormal transport, metabolism or function of NACP/alpha-synuclein appears to impair synaptic function, which induces, at least in part, neuronal degeneration in several neurodegenerative diseases.
Iwai
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Neuroscience Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. iwai@yamanouchi.co.jp
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000032:analysis; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000737:chemistry / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics; D058225:Plaque, Amyloid / Q000737:chemistry; D016415:Sequence Alignment; D013569:Synapses / Q000737:chemistry; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein
D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051845:gamma-Synuclein