A biological mechanism for depression

Summary: People with depression have increased amounts of tubulin in lipid rafts compared to those without the disorder.

Source: University of Illinois

University of Illinois at Chicago researchers report that in depressed individuals there are increased amounts of an unmodified structural protein, called tubulin, in lipid rafts — fatty sections of a cell membrane — compared with non-depressed individuals.

Their findings are published in the Journal of Neuroscience.

Tubulin is part of a protein complex that provides structure to cells. This complex also is involved in binding a specific protein called Gs alpha, or Gsa, which is a signaling molecule that conveys the action of neurotransmitters like serotonin.

Previous work established that high levels of Gsa were in the lipid rafts of depressed individuals and that Gsa lost effectiveness when in those lipid rafts. Gsa moved out of the lipid rafts after treatment with antidepressants or after using a drug inhibitor for histone deacetylase 6 (HDAC-6) — an enzyme that removes modifications from tubulin — suggesting a role of tubulin in depression as well.

Mark Rasenick, UIC professor of physiology and psychiatry at the College of Medicine, and colleagues analyzed post-mortem brain tissue from individuals with and without a diagnosis of depression to determine the location and degree of modified tubulin. A subgroup for depression also included individuals who died by suicide.

“While some studies suggest that there are differences between depressed individuals who died by suicide and those that did not, we observed a profound decrease in the extent of acetylated tubulin in lipid raft membranes from brains of all depressed subjects,” said Rasenick, who is also a research career scientist at the Jesse Brown Veteran Affairs Medical Center.

In all groups, there were no significant changes in the amounts of modified alpha tubulin, HDAC-6, or alpha tubulin acetyltransferase 1 — a protein that adds modifications to tubulin. However, there was less modified tubulin found in the lipid rafts of both depression groups versus the non-depressed group. According to Rasenick, the data suggest that diminished tubulin acetylation may be essential in harnessing Gsa to lipid rafts during depression. Antidepressants reverse this process and allow fuller function of Gsa and the neurotransmitters that activate it.

This shows a depressed man
Previous work established that high levels of Gsa were in the lipid rafts of depressed individuals and that Gsa lost effectiveness when in those lipid rafts. Image is in the public domain.

PAX Neuroscience Inc., a company created by Rasenick, researches how Gsa localization could be a diagnostic biomarker in blood cells to identify individuals with depression. Now the company will explore tubulin-related depression therapeutics and diagnostics. This may add new approaches to therapy and create diagnostic platforms to determine, in just a few days, whether an antidepressant is working.

“This work is important because half of the people who appear to be suffering from depression don’t seek treatment,” Rasenick said. “This is likely due to the social stigma surrounding people with psychiatric problems. But having an identified biological basis for depression could help people to realize that depression is not ‘their failure’ and allow them to treat it like any other illness.”

Harinder Singh, Justyna Chmura, Runa Bhaumik and Ghanshyam Pandey from UIC were co-authors.

Funding: Funding was provided by grants and awards from the U.S. Department of Veteran Affairs (BX001149 and BX 004475), the National Institutes of Health (RO1AT009169, R21 NS 109862 and RO1MH106565) and the American Heart Association (16POST27770113).

About this depression research article

Source:
University of Illinois
Media Contacts:
Jackie Carey – University of Illinois
Image Source:
The image is in the public domain.

Original Research: Closed access
“Membrane-associated α-tubulin is less acetylated in postmortem prefrontal cortex from depressed subjects relative to controls: cytoskeletal dynamics, HDAC6 and depression”. by Harinder Singh, Justyna Chmura, Runa Bhaumik, Ghanshyam N. Pandey and Mark M. Rasenick.
Journal of Neuroscience doi:10.1523/JNEUROSCI.3033-19.2020

Abstract

Membrane-associated α-tubulin is less acetylated in postmortem prefrontal cortex from depressed subjects relative to controls: cytoskeletal dynamics, HDAC6 and depression

Cytoskeletal proteins and post-translational modifications play a role in mood disorders. Post-translational modifications of tubulin also alter microtubule dynamics. Furthermore, tubulin interacts closely with Gαs, the G-protein responsible for activation of adenylyl cyclase. Postmortem tissue derived from depressed suicide brain showed increased Gαs in lipid-raft domains compared to normal subjects. Gαs, when ensconced in lipid-rafts, couples less effectively with adenylyl cyclase to produce cAMP and this is reversed by antidepressant treatment. A recent in-vitro study demonstrated that tubulin anchors Gαs to lipid-rafts and that increased tubulin acetylation (due to HDAC-6 inhibition) and antidepressant treatment decreased the proportion of Gαs complexed with tubulin. This suggested that deacetylated-tubulin might be more prevalent in depression. This study, examined tubulin acetylation in whole tissue homogenate, plasma-membrane and lipid-raft membrane domains in tissue from normal control (NC) subjects, depressed suicides and depressed non-suicides (human males/females). While tissue homogenate showed no changes in tubulin acetylation between control, depressed suicides and depressed non-suicides, plasma-membrane associated tubulin showed significant decreases in acetylation from depressed-suicides and depressed-non-suicides compared to controls. No change was seen in expression of the enzymes responsible for tubulin acetylation or deacetylation. These data suggest that during depression, membrane localized tubulin maintains a lower acetylation state, permitting increased sequestration of Gαs in lipid-raft domains, where it is less likely to couple to adenylyl cyclase for cAMP production. Thus, membrane tubulin may play a role in mood disorders which could be exploited for diagnosis and treatment.

Significance Statement

There is little understanding about the molecular mechanisms involved in the development of depression and in severe cases, suicide. Evidence for the role of microtubule modifications in progression of depressive disorders is emerging. These postmortem data provide strong evidence for membrane tubulin modification leading to reduced efficacy of the G protein, Gsα, in depression. This study reveals a direct link between decreased tubulin acetylation in human depression and the increased localization of Gαs in lipid-raft domains responsible for attenuated cAMP signaling. The evidence presented here suggest a novel diagnostic and therapeutic locus for depression.

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