Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy.
Decreased vesicular storage and aldehyde dehydrogenase activity in multiple system atrophy.
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DOI：
10.1016/j.parkreldis.2015.03.006
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发表时间：
2015-06
影响因子：
4.1
通讯作者：
Mash DC
中科院分区：
文献类型：
--
作者：
Goldstein DS;Sullivan P;Holmes C;Kopin IJ;Sharabi Y;Mash DC
帕金森病（PD）和多系统萎缩（MSA）有一些共同的神经病理表现（黑质纹状体多巴胺能病变，α -突触核蛋白沉积），但没有其他共同的神经病理表现（PD的路易体，MSA的胶质细胞质包涵体）。在帕金森病中，囊泡储存缺陷和残留多巴胺能末端的醛脱氢酶（ALDH）抑制，导致有毒多巴胺（DA）代谢物3,4-二羟基苯乙醛（DOPAL）的积累。在这项研究中，我们询问MSA是否涉及类似的异常神经化学模式。在病理证实的终末期MSA （N=15）、散发性PD （N=17）和对照组（N=18）患者的纹状体和额叶皮质组织中测定DA及其主要神经元代谢物3,4-二羟基苯基乙酸（DOPAC）、去甲肾上腺素（NE）及其主要神经元代谢物3,4-二羟基苯基乙二醇（DHPG）、儿茶酚胺前体DOPA和DOPAL。与对照组相比，MSA组和PD组的壳核DA（分别减少96%和93%，p<0.0001）、DOPAC（分别减少97%和95%，p<0.0001）、NE（分别减少91%和74%，p<0.0001）和DHPG（分别减少81%和74%，p<0.0001）均有相似的降低。MSA组和PD组DOPAL:DA比值分别为对照组的2.3和3.5倍，DHPG:NE比值分别为对照组的3.1和2.6倍，DOPAC:DOPAL比值分别下降61%和74%。在两种疾病中，皮质NE和DHPG均下降，而DA和DOPAC未见下降。MSA和PD涉及儿茶酚胺代谢谱，表明囊泡储存受损，ALDH活性降低和DOPAL积聚，这可能是儿茶酚胺神经元死亡的共同途径的一部分。通过干扰儿茶酚醛的产生或作用来靶向这一途径是一种新的治疗方法。
Parkinson disease (PD) and multiple system atrophy (MSA) share some neuropathologic findings (nigrostriatal dopaminergic lesion, alpha-synuclein deposition) but not others (Lewy bodies in PD, glial cytoplasmic inclusions in MSA). In PD evidence has accrued for a vesicular storage defect and aldehyde dehydrogenase (ALDH) inhibition in residual dopaminergic terminals, resulting in accumulation of the toxic dopamine (DA) metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL). In this study we asked whether MSA entails a similar abnormal neurochemical pattern. DA and its main neuronal metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), norepinephrine (NE) and its main neuronal metabolite 3,4-dihydroxyphenylglycol (DHPG), the catecholamine precursor DOPA, and DOPAL were measured in striatal and frontal cortical tissue from patients with pathologically proven end-stage MSA (N=15), sporadic PD (N=17), and control subjects (N=18). Compared to the control group, the MSA and PD groups had similarly decreased putamen DA (by 96% and 93%, p<0.0001), DOPAC (97% and 95%, p<0.0001), NE (91% and 74%, p<0.0001), and DHPG (81% and 74%, p<0.0001). In the MSA and PD groups, ratios of DOPAL:DA were 2.3 and 3.5 times control and DHPG:NE 3.1 and 2.6 times control, while DOPAC:DOPAL ratios were decreased by 61% and 74%. In both diseases cortical NE and DHPG were decreased, while DA and DOPAC were not. MSA and PD entail a catecholamine metabolic profile indicating impaired vesicular storage, decreased ALDH activity, and DOPAL buildup, which may be part of a common pathway in catecholamine neuronal death. Targeting this pathway by interfering with catecholaldehyde production or effects constitutes a novel treatment approach.
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影响因子：
3.7
作者：
Williams, SM;Goldman-Rakic, PS
通讯作者：
Goldman-Rakic, PS
影响因子：
4.1
作者：
Rees, Jennifer N.;Florang, Virginia R.;Doorn, Jonathan A.
通讯作者：
Doorn, Jonathan A.
帕金森病中有毒多巴胺代谢物 DOPAL 积累的决定因素。
影响因子：
4.7
作者：
Goldstein DS;Sullivan P;Holmes C;Miller GW;Alter S;Strong R;Mash DC;Kopin IJ;Sharabi Y
通讯作者：
Sharabi Y
影响因子：
--
作者：
DelleDonne, Anthony;Klos, Kevin J.;Dickson, Dennis W.
通讯作者：
Dickson, Dennis W.
影响因子：
2.5
作者：
Wakabayashi, K;Yoshimoto, M;Takahashi, H
通讯作者：
Takahashi, H