To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.

Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of ␤-amyloid and ␣-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human ␤-amyloid peptides, ␣-synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before ␣-synuclein singly tg mice, and showed prominent agedependent degeneration of cholinergic neurons and presynaptic terminals. They also had more ␣-synuclein-immunoreactive neuronal inclusions than ␣-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in ␣-synuclein singly tg mice. ␤-Amyloid peptides promoted aggregation of ␣-synuclein in a cell-free system and intraneuronal accumulation of ␣-synuclein in cell culture. ␤-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of ␣-synuclein and exacerbating ␣-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of ␤-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.A ging is a major risk factor for neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and the number of people with these conditions is increasing rapidly. In the United States alone, an estimated 4 million people have AD and at least one million have PD. Within the next 40-50 years, these numbers are projected to increase to over 8 million for AD and to 4 million for PD. Each neurodegenerative disease appears to have a predilection for specific brain regions and cell populations. However, human cases with clinical and neuropathological features of both AD and PD (1-3) raise the possibility that these diseases involve overlapping pathways.Many AD patients develop signs of PD and some PD patients become demented (3). Both diseases are associated with degeneration of neurons and interneuronal synaptic connections, depletion of specific neurotransmitters, and abnormal accumulation of misfolded proteins, whose precursors participate in normal central nervous system functions (4-11). The ␤-amyloid protein precursor (APP) and ␣-synuclein (SYN) are expressed abundantly in synapses, are well conserved across species, and have been implicated in neural plasticity, learning, and memory (6,7,12). Mutations in human APP (hAPP) that increase production of hAPP-derived ␤-amyloid peptides (A␤) cause autosomal dominant forms of familial AD (FAD) (11), and expression of FAD-mutant hAPPs in neurons of transgenic (tg) mice results in the age-dependent development of AD-like central nervous system alterations (13-17). Mutations in human SYN (hSYN) that enhance hSYN aggregation have bee...

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The muscarinic receptor agonist activities of NDMC are unique among antipsychotics, and provide a possible molecular basis for the superior clinical effects of clozapine pharmacotherapy.