Department of Environmental Health, Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA 30322, USA.
Parkinsons Dis. 2011 Feb 21;2011:124165. doi: 10.4061/2011/124165.
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.
多巴胺通过囊泡单胺转运体（VMAT2；SLC18A2）被转运到突触小泡中。储存多巴胺的破坏被假设会损害帕金森病中丢失的多巴胺神经元。通过破坏多巴胺和其他单胺类物质的囊泡储存，我们创建了一种进行性的 PD 小鼠模型，该模型在黑质致密部和蓝斑中表现出儿茶酚胺神经元的丧失以及运动和非运动症状。VMAT2 表达减少 95%，VMAT2 缺陷动物的运动功能下降，嗅觉辨别能力逐渐下降，睡眠行为迹象的潜伏期缩短，胃排空延迟，年龄较小的焦虑样行为，以及进行性抑郁样表型。病理性检查显示，VMAT2 缺陷小鼠的黑质（SNpc）、蓝斑（LC）和中缝背核（DR）出现进行性神经退行性变，同时伴有α-突触核蛋白的积累。综上所述，这些研究表明，单胺类物质的囊泡储存减少以及由此导致的细胞溶质环境的破坏可能在帕金森症状和神经退行性变的发病机制中发挥作用。VMAT2 缺陷小鼠的多系统性质可能有助于开发超越多巴胺系统的治疗策略。
