VMAT2-deficient mice display nigral and extranigral pathology and motor and nonmotor symptoms of Parkinson's disease

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 -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. copyright © 2011 tonya n. taylor et al.