Dopamine is transported into synaptic vesicles by the vesicular monoamine transporter (VMAT2; SLC18A2). Disruption of dopamine storage has been hypothesized to damage the dopamine neurons that are lost in Parkinson's disease. By disrupting vesicular storage of dopamine and other monoamines, we have created a progressive mouse model of PD that exhibits catecholamine neuron loss in the substantia nigra pars compacta and locus coeruleus and motor and nonmotor symptoms. With a 95% reduction in VMAT2 expression, VMAT2-deficient animals have decreased motor function, progressive deficits in olfactory discrimination, shorter latency to behavioral signs of sleep, delayed gastric emptying, anxiety-like behaviors at younger ages, and a progressive depressive-like phenotype. Pathologically, the VMAT2-deficient mice display progressive neurodegeneration in the substantia nigra (SNpc), locus coeruleus (LC), and dorsal raphe (DR) coupled with α-synuclein accumulation. Taken together, these studies demonstrate that reduced vesicular storage of monoamines and the resulting disruption of the cytosolic environment may play a role in the pathogenesis of parkinsonian symptoms and neurodegeneration. The multisystem nature of the VMAT2-deficient mice may be useful in developing therapeutic strategies that go beyond the dopamine system. 1. Introduction Parkinson’s disease (PD) is a devastating neurodegenerative disease and is characterized by a preferential loss of dopamine neurons. PD is distinguished by the cardinal symptoms of resting tremor, rigidity, bradykinesia, and postural instability [1–3]. The incidence of PD is positively correlated with age; there is a greater than 40-fold increase in prevalence between the ages of 55 and 85 [3]. Approximately 5–10% of PD patients have a familial form of Parkinsonism with either an autosomal dominant or autosomal recessive pattern of inheritance. These familial forms are characterized by an age of onset before 40 years and a slowly progressive course [4]. Pathogenic changes in PD are extensive and, in addition to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and loss of striatal innervation, include degeneration of the norepinephrine (NE) neurons of the locus coeruleus (LC), serotonin (5-HT) neurons of the raphe nuclei, the dorsal motor nucleus of the vagus, and the peripheral autonomic nervous system, among others [3, 5, 6]. Furthermore, Lewy body pathology can also be found in the LC, nucleus basalis of Meynert, hypothalamus, cerebral cortex, and in components of the peripheral nervous system [2,
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