Huntington’s disease, which afflicted the folksinger Woody Guthrie, is a fatal, inherited neurodegenerative disorder. While subtle personality changes and diminished physical skills may occur early in the disease, it typically becomes noticeable during middle age. Later problems include dementia and chorea – jerky movements that are random and uncontrollable.
Huntington’s disease results from a gene mutation that leads to a defective form of the huntingtin protein. The mutation is dominant, meaning that a child of an affected parent has a 50 percent chance of inheriting Huntington’s. And since the defective protein is present in all of a person’s cells, the disease causes problems in the brain and throughout the body.
“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.”
All cells rely on several different mechanisms to break down “old” proteins and other components and recycle them. Collectively known as autophagy (literally, “self-eating”), these processes keep cells clean and uncluttered and provide them with replacement parts that will function better.
In a normal cell (above), a membranous structure known
as an autophagosome collects cellular debris and
delivers it to an enzyme-filled bag called a lysosome
for digestion. But in Huntington’s disease (below),
defective huntingtin proteins (in purple) stick to
the inner layer of the autophagosome, preventing it
from collecting debris. The autophagosome arrives
empty at the lysosome, allowing debris to accumulate
to toxic levels inside the cell.Dr. Cuervo and her team had previously shown that a glitch in autophagy may trigger Parkinson’s disease by allowing a toxic protein to accumulate. She suspected that something similar was going on in Huntington’s disease. After studying two mouse models of Huntington’s disease as well as lymphoblasts (white cells) from people with the disease, she and her team found that the mutated huntingtin protein was sabotaging the cell’s garbage-collecting efforts.
One mechanism for cleaning up cells involves forming a membrane around the protein or other cellular structure requiring removal. These “garbage bags” (more formally known as autophagosomes) then travel to enzyme-filled sacs known as lysosomes that fuse with the bags and digest their cargo. But the cleanup efforts go awry in Huntington’s disease.
Dr. Cuervo and her team found that the defective huntingtin proteins stick to the inner layer of autophagosomes, preventing them from gathering garbage. The result: Autophagosomes arrive empty at the lysosomes; and cellular components that should be recycled instead accumulate, causing toxicity that probably contributes to cell death.
This finding, Dr. Cuervo noted, shows that activating the lysosomes of cells – one of the proposed treatments for Huntington’s disease – won’t do any good.
“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.”
The paper, “Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease,” appears in the April 11 online issue of Nature Neuroscience. The research was initiated by Marta Martinez-Vicente, Ph.D., a postdoctoral fellow in Dr. Cuervo’s lab, who is now at the Institute of Neuropathology in Barcelona, Spain. Esther Wong, Ph.D., currently a postdoctoral fellow with Dr. Cuervo, continued and completed the research. Other Einstein researchers involved in the study were Hiroshi Koga, Ph.D., Susmita Kaushik Ph.D., and Esperanza Arias Ph.D. This work was done in collaboration with the team of Dr. David Sulzer at Columbia University Medical School.