Huntington’s disease (HD) is an incredibly debilitating neurodegenerative disorder. Currently, there is no treatment that effectively reverses the progression of the disease or delays its onset. Huntington’s is a particularly difficult diagnosis because it is an autosomal dominant degenerative disease, meaning that any child of an affected parent has a 50% chance of inheriting the disease. Most children who inherit the disease have inevitably watched their parents battle with it.
HD manifests in movement, psychiatric, and cognitive symptoms. In a now famous account of a morning in 1968, the mother of the famous researcher Dr. Nancy Wexler was reporting for jury duty in Los Angeles when a police officer mistakenly took her jerky, uncoordinated staggering for public intoxication. He asked her whether she was ashamed of drinking so early in the morning, when in fact she was showing signs of the early chorea, the abnormal involuntary movements associated with HD. Soon after her mother was diagnosed with HD, Dr. Wexler decided to devote the rest of her life to the study of HD.
A crucial insight into the disease came in 1993 when Dr. Nancy Wexler identified the Huntington’s disease gene on human chromosome 4. This was no easy task! Beginning in 1979, she traveled to Venezuela with a team of researchers to collect blood samples from over 4,000 individuals with the disease. By tracking family histories and analyzing their DNA, Nancy and her team identified the disease-causing gene and this genetic disease. Nancy herself had a 50-50 chance of inheriting the disease from her mother and has not shown symptoms of the disease. The huntingtin gene, HTT, in individuals with the disease has an expansion of three CAG nucleotide bases that are repeated too many times. This is known as a trinucleotide repeat disorder.
Another facet of HD is the observation that neurons accumulate abnormal protein aggregates. Research recently published in Nature Neuroscience indicates that the mutant form or pathogenic version of huntingtin (mHTT) can spread the pathology from cell to cell, infecting other cells with the misfolded version of the protein. The research team observed that mHTT is capable of being transferred transneuronally, that is between or across neighboring neurons. In a clever experiment, they used botulinum neurotoxins (BoNTs) to inactivate critical players in the synaptic vesicle fusion machinery, SNAP25 and VAMP2. When this transynaptic activity was blocked, mHTT was not spread to human neurons. Transneuronal propagation of mHTT contributed to neuronal impairments and is know thought to be an underestimated player contributing to the degeneration associated with Huntington’s disease.
This study suggests that mutant huntintin can spread from neuron to neuron. The researchers on this project demonstrated that neurons genetically engineered to model the neuropathology of Huntington’s disease can cause healthy neurons derived from human stem cells to acquire mutant huntingtin. Evidence is mounting for a case that degenerative diseases share an underlying misfolded protein problem. Tau in Alzheimer’s disease, SOD1 in ALS, and a-synuclein in Parkinson’s all spread throughout the brains of afflicted individuals. It is thought that misfolded proteins spread throughout the brain in a disease-specific pattern to affect specific neural networks. This study for the first time offers insight into how mutant huntingtin moves across synapses to spread the neuropathology.
Watch this video for more details on Nancy Wexler’s work in Venezuela:
Pecho-Vrieseling E., Sascha Fuchs, Dorothee Bleckmann, Maria Soledad Esposito, Paolo Botta, Chris Goldstein, Mario Bernhard, Ivan Galimberti, Matthias Müller & Andreas Lüthi & (2014). Transneuronal propagation of mutant huntingtin contributes to non–cell autonomous pathology in neurons, Nature Neuroscience, 17 (8) 1064-1072. DOI: http://dx.doi.org/10.1038/nn.3761
“An Interview with Dr. Nancy Wexler: Discovering the Huntington Disease Gene” at newshd.net
Images by Jooyeun Lee.