Huntington’s Breakthrough

pathology microscopeHuntington’s disease a relatively rare, yet nonetheless devastating, hereditary condition whose effects have been described as a combination of Alzheimer’s, Parkinson’s and ALS.  Because of its particularly devastating symptoms, it’s the subject of plenty of scientific investigation.  I recently read about one study at Johns Hopkins where researchers found evidence that disruptions in the flow of cellular materials in and out of a cell’s nucleus could be the direct cause of brain cell death in Huntington’s disease.  The researchers, working with mouse, fly and human cells and tissue, concluded that drugs designed to clear up these disruptions could save cells, and be used to treat other neurodegenerative diseases.  

With these results, the researchers believe that they’ve found one root behind Huntington’s and other neurodegenerative diseases, and in turn how they can be treated.  Two years prior, this same team of researchers discovered how one gene mutation, which is implicated in 40 percent of inherited ALS cases and 25 percent of inherited frontotemporal dementia cases, is responsible in disrupting transport in and out of the nucleus of neurons, in turn leading to the cell’s death.  This mutant gene makes RNA molecules, which stick to a transport protein called RanGAP1, which helps move molecules through passageways in the nucleus to let proteins and genetic material flow in and out of it.  This same mutation is also the most common cause of another disorder, whose symptoms are similar to Huntington’s.  Discovering this link, the researchers took on the task of investigating whether problems with nuclear transport and pores also occurred in neurons with Huntington’s.  

Huntington’s disease is caused by a mutation in the Huntingtin protein, which results in too many repeats of the amino acid glutamine and in turn makes the protein sticky and clumpy.  For their work, the researchers used two separate models of the disease: one with a human version of the mutant protein and another with an aggressive form of the disease that only contains the first portion of the mouse protein.  Through antibodies with glowing markers, researchers saw that the mutant protein clumped in the same part of the cell as abnormal clumps of RanGAP1, as well as two other abnormal clumps of nuclear pore proteins: NUP88 and NUP62.  Since mutations in NUP62 were shown by other researchers to cause an infantile form of Huntington’s, this finding was particularly interesting.  

To delve deeper into the nuclear transport’s role in Huntington’s, researchers took lab-grown mouse neurons and used chemical switches to either activate both an additional healthy copy of the RanGAP1 gene and a mutant version of Huntingtin, just turn on the mutant Huntingtin or just turn on the healthy version of Huntingtin.  After measuring cell death, they found that neurons with the healthy version had the lowest percentile of neurons dying off, possibly because some of the extra-healthy RanGAP1 introduced into diseased cells wasn’t bound up to the mutant Huntingtin.  They then examined cell death in cultured neurons with a healthy or mutant form of Huntingtin, or with a mutant form that was treated with small amounts of the experimental drug KPT-350, which prevents the nuclear export protein Exportin-1 from shuttling proteins out of the nucleus.  Once again, those with the healthy version of Huntingtin had the lowest percent die off, suggesting that blocking nuclear export prevented cells from dying and counteracted the defects of mutant Huntingtin.  

There are, according to researchers, an average of 2000 nuclear pores in every cell, and each individual nuclear pore is made up of multiple copies of over 30 different proteins.  Nuclear pores on neurons and other types of brain cells are made up of different combinations of these different proteins, which could be critical in various neurodegenerative diseases.  The researchers are now looking to answer this questions with a new mouse model that will allow them to isolate nuclear pore proteins from different cell types in the mouse brain and identify whether these components are different.