Treatment of Catecholaminergic Neurodegeneration

点击翻译按钮获取中文摘要

(A) Alpha-Synuclein (AS) deposition in sympathetic nerves in genetic Parkinson's disease (PD): PD entails AS buildup outside the brain in sympathetic noradrenergic nerves. In collaboration with Derek Narendra (Neurogenetics Branch) we compared magnitudes of intra-neuronal AS deposition across genetic forms of PD. AS deposition in sympathetic nerves was measured by the AS-tyrosine hydroxylase (TH) colocalization index in skin biopsies. SNCA, DJ-1, LRRK2, and GBA mutations were found to be associated with high AS-TH colocalization indexes, whereas PRKN mutations were not. Calculating AS-TH colocalization indexes in skin biopsies may be informative for identifying the most appropriate candidates for experimental therapeutic trials targeting AS (PMID 34076298). (B) Animal model to test the catecholaldehyde hypothesis: With collaborators at the Tel Aviv University we found that administration of the pesticide rotenone reproduces the abnormal brain neurochemical pattern found in PD, including buildup of the autotoxic catecholaldehyde 3,4-dihydroxyphenylacetaldehyde (DOPAL. We are testing whether decreasing DOPAL formation and oxidation prevents the abnormal neurochemical pattern and associated neurobehavioral abnormalities in this model (PMID 34842277). (C) Computational modeling to predict responses to treatment in 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. We extended on a previously published computational model that incorporates harmful interactions of the dopamine metabolite 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. The model predicts that inhibiting DOPAL production at the transition from homeostasis to dyshomeostasis should substantially delay the onset of symptomatic LBDs. 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). (D) Diagnosis and treatment of Menkes disease: Menkes disease is a rare disorder of copper metabolism that usually is lethal in childhood. The enzyme that converts dopamine to norepinephrine contains and requires copper. We are collaborating with investigators at the Ohio State University on animal models of gene therapy treatments for Menkes disease, with a view to a future clinical trial. We also have in place a Cooperative Research and Development Agreement regarding treating OH with the norepinephrine pro-drug L-thre-3,4-dihydroxyphenylserine in Menkes disease patients. We continue to offer as a public service diagnostic assays of plasma levels of catechols in newborns at risk of Menkes disease, via our CLIA-certified laboratory. (E) Atomoxetine to treat cognitive dysfunction inhibits catecholamine reuptake in the human brain: The drug atomoxetine inhibits the reuptake of norepinephrine released from neurons in the brain and periphery and is being tested in people with mild cognitive dysfunction. With collaborators at Emory we found that atomoxetine treatment produces a cerebrospinal fluid neurochemical pattern consistent with decreased reuptake of both norepinephrine and dopamine in the brain (PMID 34919634). (F) Epidural spinal cord stimulation for low blood pressure (hypotension) in patients with spinal cord injury: In collaboration with investigators at the Univ. of Louisville we are evaluating effects of epidural spinal cord stimulation on plasma levels of catecholamines and related compounds in people with OH after spinal cord injury. (G) LC-MS/MS for catecholamine-related compounds: Biochemical assays of DOPAL and DOPEGAL by liquid chromatography with electrochemical detection are limited technologically. To document effects of experimental therapeutic measures on DOPAL and DOPEGAL levels, liquid chromatography with tandem and time of flight mass spectrometry (LC-MS/MS) seems superior. This methodology could also be used to identify coffee-related catechols in human plasma. Under a technology transfer agreement we are exploring whether a commercially available LC-MS/MS system validly measures plasma DOPAL and DOPEGAL.