Protein sorting in neurons protects against neurodegenerative diseases

As a sorting machine in an assembly line, a molecule called VPS35 detects and removes defective proteins from neurons. And along with other quality control processes, the VPS35 system contributes greatly to the protection of 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 releases the brain of a potentially harmful protein called tau, which otherwise accumulates and contributes to neurodegenerative disorders, including Alzheimer's disease.

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

"An important part of what VPS35 does is sort and transport the dysfunctional proteins to the degrading sites," said Principal Investigator Domenico Praticò, MD, North Star Foundation Scott Richards North Star Chair, Professor to the Departments of Pharmacology and Microbiology and Director of the Alzheimer Center at the Lewis Katz Temple School of Medicine (LKSOM).

The accumulation of defective proteins in neurons is a common feature of Alzheimer's disease, Parkinson's disease and several other neurodegenerative conditions. Tau is one of the main proteins to accumulate in the brain and causes damage to these diseases, thus creating a condition called tauopathy.

Earlier work conducted by other researchers had shown that the function of VPS35 was altered in Alzheimer's disease and that the activity of VPS35 was reduced in the brains of patients with the disease of D & # 39; 39; Alzheimer. The relationship between the activity of VPS35 and the accumulation of tau was largely unexplored.

"We specifically asked if the VPS35 system was important to eliminate defective tau proteins," Dr. Praticò said. To answer this question, his team of researchers examined the brain tissue of patients with Progressive Supra Nuclear Palsy (PSP) or Picks Disease. Unlike Alzheimer's disease, in which the accumulation of tau is secondary to that of beta-amyloid, in PSP and Picks disease, tau protein is the only protein to form deposits in the body. brain.

The analyzes revealed that the brains of patients with PSP and Pick's disease had VPS35 levels 50% lower than control subjects. When researchers deliberately modified in vitro VPS35 levels in neurons affected by tauopathy, they discovered that they could directly control the accumulation of tau, implicating for the first time the involvement of VPS35 in tauopathy. The VPS35-dependent effect on tau protein was mediated by the activity of cathepsin D, an enzyme specialized in protein degradation.

Dr. Praticò's team also conducted experiments on mice with tau accumulation. Negative regulation of VPS35 in these animals has exacerbated memory and learning disorders and has been associated with deterioration of motor function. In addition, the reduction of VPS35 resulted in a loss of synaptic integrity between neurons in the animal brain, significantly damaging neuronal communication.

"When the tau persists in cells, it's very bad for synapses, places where neurons meet and exchange signals," Dr. Praticò explained. "In the animals studied, there was a loss of synaptic connectivity when the activity of VPS35 was reduced, resulting in the types of cognitive and motor deterioration, including memory loss and learning abilities, observed in patients with human tauopathy. "

The discovery of the involvement of cathepsin D shed further light on the relationship between VPS35 and tau. "Without VPS35, cathepsin D does not degrade tau protein, letting it accumulate in the brain," Dr. Pratico said.

Dr. Praticò's team then plans to study the possibility of using a drug to deliver VPS35 in the context of neurodegenerative disease. "The approach would be unique: instead of targeting an enzyme, as other small molecules do, we would target a real mechanism, which should be more viable," he said.