2022-08-31| R&D

Human Skin Cells Reprogramming Creates New Neurodegenerative Model For Huntington’s Disease

by Nai Ye Yeat
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Researchers at Lund University in Sweden have developed a new animal model to study Huntington’s disease, an age-related brain disorder, and the findings were published in Journal Brain

With the novel approach applied, scientists successfully identified a distinct subcellular autophagy impairment in patient-derived Huntington’s disease neurons and provided a new insight for future development of autophagy activation therapies.

Related article: Spotlight: New Gene Therapies on the Horizon for the Treatment of Neurogenetic Diseases

A Fatal Disease with No Cure 

Huntington’s disease is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Clinically, it is characterized by involuntary movements together with cognitive impairment, psychiatric disturbances as well as metabolic and sleep problems due to extensive cell impairment and death within the CNS. The pathology is closely related to genetics and age in combination, and it is often diagnosed around the age of 50. Current treatments could help manage the symptoms of Huntington’s disease; however, the physical, mental and behavioral decline associated are irreversible.

HTT is ubiquitously expressed, but a mutated Huntingtin allele (mHTT) will result in the dysfunction and death of neurons, specifically in the striatum and cortex area. Mutant HTT tends to aggregate and form insoluble protein inclusions, although the underlying mechanisms of neuronal dysfunction and ultimately cell death remain unknown.

Unsatisfied Need for Age-Dependent Disease Model

To develop disease-modifying treatments for Huntington’s disease, the molecular and cellular basis for the pathology and the age-related disease process have become the main interests of scientists right now.

However, the challenge is that no Huntington’s disease model is available to preserve its age-dependent nature, as rodent and cellular models poorly recapitulate the disease as seen in aging humans. Hence, the team came up with a brilliant idea to generate induced neurons through direct reprogramming of human skin fibroblasts. 

The team collected fibroblasts through skin biopsies from 10 individuals diagnosed with Huntington’s disease and 10 healthy controls, and directly induced neuron conversion of fibroblasts in order to retain the biological age of the cells. Upon transduction, the fibroblasts rapidly developed a clear neuronal morphology with a reduction in the size of both the nuclei and cell body, accompanied by the formation of long, elaborate neurites. A couple of weeks later, the reprogrammed fibroblasts transformed into mature induced neurons and started to express the neuronal markers MAP2 and TAU. In addition, there was no difference in the rate of cell death between the control and transformation groups at four weeks, suggesting a stable model ready to use.

With the novel model developed, the scientists are able to uncover the relationship between autophagy impairment and Huntington’s disease and provide insight for the future development of autophagy activation therapies. 

The novel method has been applied for a patent and is currently licensed to the New York Stem Cell Foundation. Furthermore, this is not only a breakthrough in Huntington’s disease study, but also provides an alternative model for other neurodegenerative disorders, especially Parkinson’s and Alzheimer’s.

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