The "Sick-but-not-Dead" Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases

Abstract

The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.

Fig. 1

Lewy bodies. The left panel shows an intracellular Lewy body stained with hematoxylin/eosin from a patient with pure autonomic failure (PAF). The right panel shows an immunofluorescence microscopic image of an extracellular Lewy body and nearby Lewy neurite from sympathetic ganglion tissue of a patient with Parkinson’s disease and orthostatic hypotension. In the right panel, red corresponds to immunoreactive tyrosine hydroxylase (TH), green α-synuclein (AS), blue DAPI to stain nuclei, and yellow TH-AS colocalization. Note TH in the center of the Lewy body and colocalized TH and AS in the halo. The Lewy neurite contains AS. Scale bar 10 μm. (Image courtesy of R. Isonaka.)

Fig. 2

Sites of functional abnormalities of catecholamine synthesis, storage, release, recycling, and metabolism in myocardial sympathetic nerves in Lewy body diseases. Reactions are in italics and amounts of reactants in plain text. Font sizes correspond roughly to amounts of reactants. Green arrows indicate dopamine (DA) synthesis and blue arrows norepinephrine (NE) vesicular uptake and leakage. Red X marks placed to indicate sites of abnormalities in residual sympathetic nerves in Lewy body diseases. Application of a kinetic model to previously published data revealed three types of abnormal intraneuronal processes in the Lewy body disease group—(a) attenuated catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, (b) impaired vesicular sequestration of cytoplasmic catecholamines, reflecting the balance of vesicular uptake versus leakage, and (c) inefficient recycling of released NE by reuptake through the cell membrane NE transporter. ALDH, aldehyde dehydrogenase; AR, aldehyde/aldose reductase; Cys-DA, 5-S-cysteinylDA; Cys-DOPA, 5-S-cysteinyl DOPA; DAc, cytoplasmic DA; DBH, dopamine-β-hydroxylase; DHPG, 3,4-dihydroxyphenylglycol; DOPAc, cytoplasmic DOPA; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPEGAL, 3,4-dihydroxyphenylglycolaldehyde; DOPAL, 3,4-dihydroxyphenylacetaldehyde; DOPET, 3,4-dihydroxyphenylethanol; EPI, epinephrine; LAAAD, L-aromatic-amino-acid decarboxylase; MAO, monoamine oxidase; NEc, cytoplasmic NE; NEe, NE in the extracellular fluid; NESO, NE entering the cardiac venous drainage; TH, tyrosine hydroxylase; TYR, tyrosine; TYRc, cytoplasmic TYR; U1 = Uptake-1, neuronal uptake; U2 = Uptake-2, extraneuronal uptake; VMAT, vesicular monoamine transporter.

Fig. 3

Overview of the sources and fate of intraneuronal catecholamines, with emphasis on spontaneous and enzymatic oxidation of catechols. Dopamine (DA) is synthesized in the neuronal cytoplasmic via tyrosine hydroxylase (TH) acting on tyrosine to form 3,4-dihydroxyphenylalanine (DOPA) and then L-aromatic-amino-acid decarboxylase (LAAAD) acting on DOPA. Most of cytoplasmic DA is taken up into vesicles via the vesicular monoamine transporter (VMAT). Dopamine-β-hydroxylase (DBH) in the vesicles catalyzes the conversion of DA to norepinephrine (NE). DA and NE in the cytoplasm are subject to oxidative deamination catalyzed by monoamine oxidase-A (MAO-A) in the outer mitochondrial membrane to form 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL). DOPAL is converted to 3,4-dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH), and DOPEGAL is converted to 3,4-dihydroxyphenylglycol (DHPG) via aldehyde/aldose reductase (AR). Most of vesicular NE released by exocytosis is taken up into the cytoplasm via the cell membrane NE transporter (NET). DOPA can undergo spontaneous oxidation to DOPA-quinone (DOPA-Q), resulting in formation of 5-S-cysteinylDOPA (Cys-DOPA), and DA can undergo spontaneous oxidation to DA-quinone (DA-Q), resulting in formation of 5-S-cysteinylDA (Cys-DA).

Fig. 4

Alternative routes by which dopamine (DA) oxidation may modify α-synuclein. Most of cytoplasmic DA is taken up into vesicles via the vesicular monoamine transporter (VMAT), but a minority undergoes oxidation, by two routes (red numbers in boxes). In route 1, DA is oxidized to form DA-quinone (DA-Q), with subsequent interactions with α-synuclein directly or via various further products of DA-Q, including 5-S-cysteinyldopamine (Cys-DA). In route 2, DA is oxidized enzymatically by monoamine oxidase-A (MAO-A) in the outer mitochondrial membrane to form 3,4-dihydroxyphenylacetaldehyde (DOPAL) and hydrogen peroxide (H2O2). Cu(II) promotes the oxidation of DA and DOPAL. Formation of DA-Q and DOPAL-Q is associated with generation of superoxide radicals (O2−•). DOPAL is metabolized by aldehyde dehydrogenase (ALDH) to form 3,4-dihydroxyphenylacetic acid (DOPAC), which exits the cell.

Fig. 5

Sites of action of a combination of a monoamine oxidase inhibitor (MAOI) and N-acetylcysteine (NAC) in testing the catecholaldehyde hypothesis. Cytoplasmic DA oxidizes spontaneously to DA-quinone (DA-Q) and then several oxidation products including aminochrome and 5-S-cysteinyldopamine (Cys-DA). DOPAL oxidizes spontaneously to DOPAL-quinone (DOPAL-Q). DA oxidation products are toxic, via mitochondrial and other lesions. DOPAL reacts with hydrogen peroxide and divalent metal cations to form hydroxyl radicals, which peroxidate membrane lipids. The lipid peroxidation products 4-hydroxynonenal and malondialdehyde inhibit ALDH. DOPAL, probably via oxidation to DOPAL-Q, oligomerizes and forms quinoprotein adducts with (“quinonizes”) α-synuclein. DOPAL-induced synucleinopathy impedes vesicular functions. According to the “catecholaldehyde hypothesis,” interactions of DOPAL and α-synuclein set the stage for vicious cycles that challenge homeostasis in catecholaminergic neurons.