Marked disparity between age-related changes in dopamine and other pre-synaptic dopaminergic markers in striatum

Department of Biochemistry and Molecular Biology, Louisiana State University Health Science Center, New Orleans 70119, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 12/2003; 87(3):574-85. DOI: 10.1046/j.1471-4159.2003.02017.x
Source: PubMed


Because age-related changes in brain dopaminergic innervation are assumed to influence human disorders involving dopamine (DA), we measured the levels of several presynpatic DAergic markers [DA, homovanillic acid, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT)] in post-mortem human striatum (caudate and putamen) from 56 neurologically normal subjects aged 1 day to 103 years. Striatal DA levels exhibited pronounced (2- to 3-fold) post-natal increases through adolescence and then decreases during aging. Similarly, TH and AADC increased almost 100% during the first 2 post-natal years; however, the levels of TH and, to a lesser extent, AADC then declined to adult levels by approximately 30 years of age. Although VMAT2 and DAT levels closely paralleled those of TH, resulting in relatively constant TH to transporter ratios during development and aging, a modest but significant decline (13%) in DAT levels was observed in only caudate during aging. This biphasic post-natal pattern of the presynaptic markers suggests that striatal DAergic innervation/neuropil appears to continue to develop well past birth but appears to become overelaborated and undergo regressive remodeling during adolescence. However, during adulthood, a striking discrepancy was observed between the loss of DA and the relative preservation of proteins involved in its biosynthesis and compartmentation. This suggests that declines in DA-related function during adulthood and senescence may be explained by losses in DA per se as opposed to DAergic neuropil.

Download full-text


Available from: Yoshiaki Furukawa, Oct 13, 2014
  • Source
    • "TABLE 1. Primary Antibodies Antigen Immunogen Manufacturer, species antibody was raised in and type, catalog # Dilution Reference Tyrosine hydroxylase Denaturated tyrosine hydroxylase from rat pheochromocytoma Millipore, purified rabbit polyclonal, Cat# AB152, RRID:AB_390204 1:10,000 Hendrickson et al., 1981 Vesicular monoamine transporter 2 (VMAT2) Peptide from intracellular C-terminal region of human VMAT2 (C-TQNNIQSYPIGEDEESESD-OH) PhosphoSolutions, purified sheep polyclonal, Cat# 2200-VMAT2C, RRID:AB_2315595 1:10,000 Haycock et al., 2003; Witkovsky et al., 2004 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dopaminergic amacrine cells (DACs) release dopamine in response to light-driven synaptic inputs, and are critical to retinal light adaptation. Retinal degeneration (RD) compromises the light responsiveness of the retina, and subsequently, dopamine metabolism is impaired. As RD progresses, retinal neurons exhibit aberrant activity, driven by AII amacrine cells, a primary target of the retinal dopaminergic network. Surprisingly, DACs are an exception to this physiological change; DACs exhibit rhythmic activity in healthy retina, but do not burst in RD. The underlying mechanism of this divergent behavior is not known. It is also unclear whether RD leads to structural changes in DACs impairing functional regulation of AII amacrine cells. Here, we examine the anatomical details of DACs in three mouse models of human RD, to determine how changes to the dopaminergic network may underlie physiological changes in RD. By using rd10, rd1 and rd1/C57 mice we were able to dissect the impacts of genetic background and the degenerative process on DAC structure in RD retina. We found that DACs density, soma size, and primary dendrite length are all significantly reduced. Using a novel adeno-associated virus-mediated technique to label AII amacrine cells in mouse retina, we observed diminished dopaminergic contacts to AII amacrine cells in RD mice. This is accompanied by changes to the components responsible for dopamine synthesis and release. Together, these data suggest that structural alterations of the retinal dopaminergic network underlie physiological changes during RD.
    The Journal of Comparative Neurology 09/2015; DOI:10.1002/cne.23899 · 3.23 Impact Factor
  • Source
    • "However, this snDAc subgroup also shows the highest degeneration rate during aging, a fact observed in both monkeys (Kanaan et al., 2008; Collier et al., 2011) and humans (Reeve et al., 2014). In addition, the striatal distribution of the DA denervation is also similar in PD (Kish et al., 1988; Hornykiewicz, 1989) and aging (Kish et al., 1992; Haycock et al., 2003). Therefore, the difference between the DA-cell degeneration in PD and aging may be the intensity of the degeneration process more than the type of cells which degenerate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.
    Frontiers in Neuroanatomy 08/2014; 8:80. DOI:10.3389/fnana.2014.00080 · 3.54 Impact Factor
    • "and indirect evidence of decreased TH expression in SN (Fearnley and Lees 1991; Emborg et al. 1998; Rudow et al. 2008; Salvatore et al. 2009a) but no loss of striatal TH in rats (Salvatore et al. 2009a; Salvatore and Pruett 2012) or in the human lifespan (Haycock et al. 2003). In PD models, TH loss may be more severe in striatum, followed by loss of a lesser magnitude in SN at the locomotor symptom stage (Bezard et al. 2001; Sarre et al. 2004; Chu et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Compensatory mechanisms in dopamine (DA) signaling have long been proposed to delay onset of locomotor symptoms during Parkinson's disease (PD) progression until ~80% loss of striatal DA occurs. Increased striatal dopamine turnover has been proposed to be a part of this compensatory response, but may occur after locomotor symptoms. Increased tyrosine hydroxylase (TH) activity has also been proposed as a mechanism, but the impact of TH protein loss upon site-specific TH phosphorylation in conjunction with the impact on DA tissue content is not known. The tissue content of DA was determined against TH protein loss in the striatum and substantia nigra (SN) following 6-OHDA lesion in the medial forebrain bundle in young Sprague-Dawley male rats. Although DA predictably decreased in both regions following 6-OHDA, there was a significant difference in DA loss between the striatum (75%) and SN (40%), despite similar TH protein loss. Paradoxically, there was a significant decrease in DA against remaining TH protein in striatum, but a significant increase in DA against remaining TH in SN. In the SN, increased DA per remaining TH protein was matched by increased ser31, but not ser40, TH phosphorylation. In striatum, both ser31 and ser40 phosphorylation decreased, reflecting decreased DA per TH. However, in control nigral and striatal tissue, only ser31 phosphorylation correlated with DA per TH protein. Combined, these results suggest that the phosphorylation of ser31 in the SN may be a mechanism to increase DA biosynthesis against TH protein loss in an in vivo model of PD. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 01/2014; 129(3). DOI:10.1111/jnc.12652 · 4.28 Impact Factor
Show more