Sorting protein in neurons defends against neurodegenerative disease

Summary: VPS35 is a novel critical component of tau metabolism and the pathology of neurodegenerative diseases.

Source: Temple University Health System

Like a sorting machine in an assembly line, a molecule known as VPS35 detects and removes defective proteins from neurons. And similar to other quality control processes, the VPS35 system goes a long way toward protecting health, according to new work by researchers at the Lewis Katz School of Medicine at Temple University. They show for the first time that VPS35 clears the brain of a potentially harmful protein called tau, which otherwise accumulates and contributes to neurodegenerative disorders, including Alzheimer’s disease.

The new findings were published online July 9 in the journal Molecular Psychiatry.

“A major part of what VPS35 does is to sort out and transport dysfunctional proteins to degradation sites,” explained senior investigator Domenico Praticò, MD, Scott Richards North Star Foundation Chair for Alzheimer’s Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer’s Center at Temple at the Lewis Katz School of Medicine (LKSOM).

The buildup of defective proteins in neurons is a feature shared by Alzheimer’s disease, Parkinson’s disease, and several other neurodegenerative conditions. Tau is one of the major proteins to amass in the brain and cause damage in these diseases, creating a condition described as tauopathy.

Previous work by other researchers had shown that the function of VPS35 is altered in Alzheimer’s disease and that VPS35 activity is reduced in the brains of Alzheimer’s patients. The relationship between VPS35 activity and tau accumulation was largely unexplored.

“We asked specifically whether the VPS35 system is important for clearing defective tau proteins,” Dr. Praticò said. To answer this question, his team of researchers examined brain tissue from patients with either progressive supra-nuclear palsy (PSP) or Picks’ disease. Unlike Alzheimer’s disease, in which tau accumulation is secondary to that of beta-amyloid, in PSP and Picks’ disease tau is the only protein to form deposits in the brain.

Analyses revealed that the brains of PSP and Pick’s disease patients had VPS35 levels that were 50 percent lower than those of control subjects. When the researchers deliberately altered VPS35 levels in individual tauopathy-affected neurons in vitro, they discovered that they could directly control tau accumulation, for the first time implicating VPS35 in tauopathy. The VPS35-dependent effect on tau was mediated by the activity of cathepsin D, an enzyme that specializes in protein degradation.

Dr. Praticò’s team also carried out experiments in mice with tau accumulation. VPS35 downregulation in these animals exacerbated memory and learning impairment and was associated with worsened motor function. Moreover, VPS35 reduction resulted in a loss of synaptic integrity between neurons in the animals’ brains, significantly damaging neural communication.

This shows a fancy drawing of a brain

The buildup of defective proteins in neurons is a feature shared by Alzheimer’s disease, Parkinson’s disease, and several other neurodegenerative conditions. Tau is one of the major proteins to amass in the brain and cause damage in these diseases, creating a condition described as tauopathy. The image is in the public domain.

“When tau lingers in cells, it is very bad for synapses, the places where neurons meet and exchange signals,” explained Dr. Praticò. “In the animals we studied, there was a 40 to 50 percent loss in synaptic connectivity when VPS35 activity was reduced, which led to the types of cognitive and motor deterioration, including losses in memory and learning ability, seen in human tauopathy patients.”

The discovery of the involvement of cathepsin D shed additional light on the relationship between VPS35 and tau. “Without VPS35, cathepsin D does not degrade tau, leaving tau to build up in the brain,” Dr. Praticò said.

Dr. Praticò’s team plans next to investigate the possibility of using a drug to put VPS35 back to work in the context of neurodegenerative disease. “The approach would be unique. Instead of targeting an enzyme, as other small molecules have been developed to do, we would be targeting an actual mechanism, which should be more viable,” he said.

Other researchers contributing to the study include Alana N. Vagnozzi, Jian-Guo Li, Jin Chiu, and Rebecca Warfield in the Alzheimer’s Center at Temple and the Department of Pharmacology at LKSOM; and Roshanak Razmpour and Servio H. Ramirez in the Department of Pathology and Laboratory Medicine at LKSOM.

Funding: The research was funded in part by National Institutes of Health grants AG055707 and AG056689.

About this neuroscience research article

Source:
Temple University Health System
Media Contacts:
Jeremy Walter – Temple University Health System
Image Source:
The image is in the public domain.

Original Research: Closed access
“VPS35 regulates tau phosphorylation and neuropathology in tauopathy”. Alana N. Vagnozzi, Jian-Guo Li, Jin Chiu, Roshanak Razmpour, Rebecca Warfield, Servio H. Ramirez & Domenico Praticò.
Molecular Psychiatry. doi:10.1038/s41380-019-0453-x

Abstract

VPS35 regulates tau phosphorylation and neuropathology in tauopathy

The vacuolar protein sorting 35 (VPS35) is a major component of the retromer recognition core complex which regulates intracellular protein sorting and trafficking. Deficiency in VPS35 by altering APP/Aβ metabolism has been linked to late-onset Alzheimer’s disease. Here we report that VPS35 is significantly reduced in Progressive Supra-nuclear Palsy and Picks’ disease, two distinct primary tauopathies. In vitro studies show that overexpression of VPS35 leads to a reduction of pathological tau in neuronal cells, whereas genetic silencing of VPS35 results in its accumulation. Mechanistically the availability of active cathepsin D mediates the effect of VPS35 on pathological tau accumulation. Moreover, in a relevant transgenic mouse model of tauopathy, down-regulation of VPS35 results in an exacerbation of motor and learning impairments as well as accumulation of pathological tau and loss of synaptic integrity. Taken together, our data identify VPS35 as a novel critical player in tau metabolism and neuropathology, and a new therapeutic target for human tauopathies.

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