A service of Penn’s Neuroscience Graduate Group


Genetic mutations related to Huntington’s disease disrupt the transport and breakdown of unwanted materials in the cell

or, technically,
The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. [See the original abstract on PubMed]


Authors: Yvette C. Wong, Erika L. Holzbaur

Brief prepared by: Sarah Ly
Brief approved by: Isaac Perron
Section Chief: Alyse Thomas
Date posted: May 3, 2016
Brief in Brief (TL;DR)

What do we know: Healthy cells need to get rid of materials that they can no longer use. In Huntington’s disease (HD), cells aren’t able to get rid of unwanted stuff and scientists think this is one reason why the disease destroys the brain.

What don’t we know: The specific ways that HD causes cells to be unable to get rid of unwanted material.

What this study shows: In HD, what may be happening is that cells with mutated htt protein can’t transport unwanted stuff to where it needs to go because normally in a healthy cell the htt protein and its partner protein help move junk from one end of the neuron (the tip of the axon) to the other end (the cell body).

What we can do in the future because of this study: We can continue to study cell transport and find new ways to treat HD.

Why you should care: There is currently no cure for HD. By improving our understanding of what goes wrong in the brain during HD, scientists can work towards developing new treatments for the disease.

Brief for Non-Neuroscientists

Healthy cells need to get rid of materials that they can no longer use. Huntington’s disease (HD) is a devastating disease where sufferers lose brain function and are unable to control their own body movements. In the brains of patients with HD, the neurons — the main cells in the brain — aren’t able to get rid of unwanted junk or waste. Scientists believe this may be the reason why neurons die in the brain in HD. In a healthy neuron, waste gets packaged and transported from one end of the cell (the tip of the axon) back to the other end of the cell (the cell body). Scientists are still trying to figure out what specifically goes wrong in this process that causes cells to die in HD. This study shows that normal huntingtin protein helps move things from the axon to the cell body with the help of a partner protein. Thus, having abnormal huntingtin protein, which is the cause of HD, prevents cells from moving waste back to the cell body and this waste is now not efficiently degraded. This is important to know because it shows us that in HD, the problem with getting rid of junk is that the junk can’t travel to where it needs to go! If cells are no longer able to move stuff that it no longer needs to places where it can get broken down, these things can build up and cause cells to die.

Brief for Neuroscientists

Healthy cells must regularly degrade nonessential proteins in a process known as autophagy. Defects in autophagy have been implicated in the neurodegenerative disorder Huntington’s disease (HD), which is caused by a polyglutamine expansion in the huntingtin (htt) gene. The precise mechanisms that underlie autophagosomal defects in HD are not fully understood. In healthy neurons, autophagosomes form at the axon tip and are transported toward the cell body. By live-imaging cells with GFP-labeled autophagosomes, we found that both the htt protein and its adaptor protein huntingtin-associated protein-1 (HAP1) physically associate with autophagosomes in neurons and are necessary for proper retrograde transport of autophagosomes along the axon. This retrograde transport is impaired when neurons express the mutant htt protein. The expression of mutant htt in neurons is also associated with the accumulation of dysfunctional mitochondrial cargo within the autophagosomes, suggesting that defective autophagosome transport is linked to defects in autophagic degradation. The role of htt and HAP1 in promoting transport of autophagosomes may explain how mutations in htt contribute to neurodegeneration and cell death in HD.

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