Mechanisms of Catecholaminergic Neurodegeneration

National Institute Of Neurological Disorders And Stroke

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Abstract

According to the catecholaldehyde hypothesis, neurons that produce the catecholamines dopamine and norepinephrine are susceptible in Lewy body diseases (LBDs), because 3,4-dihydroxyphenylacetaldehyde (DOPAL) formed within the neurons as part of normal metabolism is an autotoxin that poses a continuous challenge to neuronal integrity. Mutations that promote DOPAL formation, increase spontaneous oxidation of DOPAL, inhibit detoxification of DOPAL, or enhance DOPAL-induced misfolding of proteins may interfere with processes that keep neurotransmitter stores within healthy bounds (homeostasis). Harmful effects of DOPAL, especially via interactions with the protein alpha-synuclein (AS), could be cumulative and progress over years. Compensatory, homeostatic adjustments that keep neurotransmitter levels within bounds eventually could give way, with rapid degeneration and death of the neurons and various manifestations resulting from catecholamine deficiency. (A) Alpha-synuclein (AS) deposition in sympathetic nerves in skin, submandibular gland (SMG), and heart in PD: A post-mortem observational study: The pathophysiological significance of AS deposition in catecholaminergic neurons, although widely suspected, has been poorly understood. In a post-mortem study we quantified the amounts of immunoreactive AS and tyrosine-hydroxylase (TH, a marker of catecholaminergic neurons) and concurrently assayed norepinephrine contents in three sympathetic noradrenergically innervated structures--skin, SMG, and myocardum--from patients with autopsy-proven PD. In all three tissues PD patients had increased AS deposition compared to age-matched controls. Norepinephrine and TH contents were normal in skin and SMG samples from PD patients, whereas in the heart, PD patients had severe norepinephrine deficiency and decreased TH. These findings suggest that in skin and SMG AS deposition may be a non-pathogenic biomarker, whereas in the heart AS in sympathetic nerves may be toxic (PMID 35260194). (B) Computational modeling reveals tri-phasic progression of LBDs: By the time a patient develops symptoms of a LBD, there is already substantial loss of catecholaminergic neurons. Identifying biomarkers of preclinical LBDs may be crucial for maximizing the effectiveness of disease-modifying treatments. The pattern of progression of catecholaminergic neurodegeneration in preclinical LBDs, however, has been unknown. We extended on a previously published computational model that incorporates harmful interactions of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) with AS. The modeling indicated tri-phasic loss of catecholamine contents, from homeostasis in the first phase to dyshomeostasis and rapid catecholamine depletion in the second phase to slow further loss in the symptomatic third phase. Empirical longitudinal neuroimaging data in both the heart and putamen of LBD patients fit with this tri-phasic pattern. Combining computational modeling with clinical laboratory biomarkers to detect preclinical disease may enable individualized predictions about disease progression and target specific intra-neuronal dysfunctions for experimental therapeutic trials in LBDs (PMID 35621196). (C) Increased striatal DOPAL in the rat rotenone model of PD: Several recent reports have indicated that PD involves multiple functional abnormalities in residual catecholaminergic neurons associated with buildup of DOPAL, the focus of the catecholaldehyde hypothesis for the pathogenetic mechanism of PD. An animal model is needed that reproduces the abnormal catecholamine neurochemical pattern and DOPAL accumulation. Adult rats received subcutaneous vehicle or the mitochondrial complex 1 inhibitor rotenone for 10 days. Compared to vehicle-treated control animals, rotenone-treated animals had reduced locomotor activity, decreased tissue dopamine concentrations, reduced indices of vesicular sequestration and of aldehyde dehydrogenase activity, and increased DOPAL levels. The rat rotenone model therefore involves functional abnormalities in catecholaminergic neurons that replicate the pattern found in PD putamen and provides a suitable in vivo platform for studying the catecholaldehyde hypothesis (PMID 34842277). (D) Liquid chromatography with tandem mass spectroscopy (LC-MS/MS) for catecholamine-related compounds: Biochemical assays of DOPAL in body fluids by liquid chromatography with electrocehmical detection are limited technologically. For further development of means to elucidate mechanisms of catecholaminergic neurodegneration by measuring levels of DOPAL, liquid chromatography with tandem mass spectroscopy (LC-MS/MS) seems necessary. Under a technology transfer agreement we are assessing whether a commercially available LC-MS/MS system measures DOPAL and 3,4-dihydroxyphenylglycolaldehyde (the catecholaldehyde of norepinephrine) sensitively and specifically.