Autophagy increases but is impaired, leading to an increase of the HD protein in the cytosol.
One of the major pathologies in Huntington's Disease is the accumulation of the toxic huntingtin protein in both the cytosol and the nucleus of the affected neurons where it causes damage leading to cellular dysfunction and cell death.
There are two methods by which cells degrade and recycle proteins. One is through the Ubiquitin Proteosome System (UPS) in which proteins which are not needed or which have misfolded are tagged for degradation by a small protein called ubiquitin. The unwanted protein is then moved into the proteosome, a barrel like protein complex, which breaks it down into amino acids that can then be recycled. The normal huntingtin protein is degraded in the cytosol through the UPS.
However, in Huntington's Disease, the UPS is unable to handle the HD protein properly. There's an alternate system of protein degradation called (macro)autophagy which literally translates as 'self eating.' In this very old cellular house cleaning process (it's found in organisms from yeast to mammals), damaged parts of the cell, pathogens, and large proteins are surrounded by autophagosomes. The autophagosomes deliver their cargo to the lysosomes by fusing with them. The lysosomes then consume the material. The mutant huntingtin protein is removed from the cytosol through autophagy. This process is unavailable in the nucleus of the cell which depends on the UPS.. One suggested strategy for treatment is to enhance autophagy to at least deal with the problems caused in the cytosol. And indeed, studies have shown an increase in autophagy occurs in response to the mutant protein.
So why is the HD protein accumulating in the cytosol?
Researchers at Albert Einstein Medical College in New York City have carefully examined the autophagy process in various cell models derived from two HD mouse models and HD patients. As did other researchers, they found an increase in autophagosomes in tissue from HD patients. They also found that the autophagosomes form normally and fuse normally with the lysosomes. In a seeming paradox, however, they found a reduction in proteolysis (the breakdown of proteins) in both the striatal and non-neuronal HD cells that they examined.
"Studies have shown that Huntington's disease occurs in part because the mutated huntingtin protein accumulates within cells and is toxic to them," said Ana Maria Cuervo, M.D., Ph.D., professor of developmental and molecular biology, of anatomy and structural biology, and of medicine at Einstein and senior author of the Nature Neuroscience study. "In our investigation of how the accumulating huntingtin protein affects the functioning of cells, we found that it interferes with the cells' ability to digest and recycle their contents."
Dr. Cuervo and her team discovered that the defective huntingtin proteins stick to the inner layer of autophagosomes, preventing them from gathering garbage. As a result, the autophagosomes arrive empty at the lysosomes. They found an enhanced binding of the HD protein with P62 at the autophagic membranes. Since P62 appears to be necessary for the autophagosomes to recognize cellular garage, this could explain the problem.
The researchers also found an increase in abnormal lipids and depolarized mitochondria which may be caused, in part at least, by the autophagosomes failure to recognize them as material (or cargo) for degradation and recycling. Their ongoing presence could contribute to the damage that leads to cell death.
This research shows that enhancing autophagy will not work as a treatment. "It doesn't matter how active your lysosomes are if they're not going to receive any cellular components to digest," she said. "Instead, we should focus on treatments to help autophagosomes recognize intracellular garbage, perhaps by minimizing their contact with the defective huntingtin protein. By enhancing the clearance of cellular debris, we may be able to keep Huntington's patients free of symptoms for a longer time."
This study is a good example of why basic research continues to be needed. At first it looked like discovering or developing drug to enhance autophagy could result in a major treatment. Then it was discovered that authophagy is available in the cytosol and not the nucleus where mutant HD does a lot of damage - still a potentially good treatment but perhaps not as powerful. Now it has been learned that the autophagosomes don't recognize and degrade the HD protein. While an autophagy-related treatment might still be a possibility, it would need to address the cargo recognition problem instead.
Quotes and graphic from the Albert Einstein College of Medicine Press Release
Continuous turnover of intracellular components by autophagy is necessary to preserve cellular homeostasis in all tissues. Alterations in macroautophagy, the main process responsible for bulk autophagic degradation, have been proposed to contribute to pathogenesis in Huntington's disease (HD), a genetic neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin protein. However, the precise mechanism behind macroautophagy malfunction in HD is poorly understood. In this work, using cellular and mouse models of HD and cells from humans with HD, we have identified a primary defect in the ability of autophagic vacuoles to recognize cytosolic cargo in HD cells. Autophagic vacuoles form at normal or even enhanced rates in HD cells and are adequately eliminated by lysosomes, but they fail to efficiently trap cytosolic cargo in their lumen. We propose that inefficient engulfment of cytosolic components by autophagosomes is responsible for their slower turnover, functional decay and accumulation inside HD cells.