Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord progressively leading to paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms. The clinical manifestations observed in ALS appear relatively late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult. Therefore, novel strategies for early diagnosis of neurodegeneration, to monitor disease progression and to assess response to existing and future treatments are urgently needed. Factually, many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. Aiming to generate an innovative human-based model to facilitate the identification of predictive biomarkers associated with the disease, we developed a unique ALS tissue-engineered skin model (ALS-TES) derived from patient’s own cells. The ALS-TES presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions. Remarkably, these abnormal skin defects, uniquely seen in the ALS-derived skins, were detected in pre-symtomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS skin model could represent a renewable source of human tissue, quickly and easily accessible to better understand the physiopathological mechanisms underlying this disease, to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early diagnosis and disease monitoring.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0181-z) contains supplementary material, which is available to authorized users.
Highlights
Among neurological disorders, neurodegenerative diseases are becoming more and more prominent because of their severity and increasing frequency in aging populations
Derived skin In order to determine if cytoplasmic TDP-43 aggregates can be detected in Amyotrophic lateral sclerosis (ALS)-TES, 7-μm thick tissue sections were prepared and stained with commercial TDP-43 polyclonal antibody
Cytoplasmic TDP-43 inclusions were only detected in our three dimensional (3D) ALS tissue-engineered skin model (ALS-TES) model and were not detected in patient’s fibroblasts alone standard two dimensional (2D) cell culture indicating that our 3D skin model is necessary to observe the described phenotype (Figure 4)
Summary
Neurodegenerative diseases are becoming more and more prominent because of their severity and increasing frequency in aging populations. The causes and pathogenic mechanisms of these diseases remain largely unknown. These diseases are currently incurable and difficult to diagnose before a late stage due to lack of efficient. The latency between the first symptoms and a formal diagnosis of ALS has remained unchanged for more than a decade and ranges from 8.0 to 15.6 months [2]. At such a late stage, a large proportion of motor neurons have already been lost. Novel discoveries of sensitive and specific biomarkers for ALS are needed to facilitate diagnosis at early stages, monitor disease progression, and assess response to existing and future treatments
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