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Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients.

Paré B, Touzel-Deschênes L, Lamontagne R, Lamarre MS, Scott FD, Khuong HT, Dion PA, Bouchard JP, Gould P, Rouleau GA, Dupré N, Berthod F, Gros-Louis F - Acta Neuropathol Commun (2015)

Bottom Line: As a result, the identification and development of disease-modifying therapies is difficult.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.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.

View Article: PubMed Central - PubMed

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 physiophatological mechanisms underlying this disease, to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early diagnosis and disease monitoring.

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Cytoplasmic TDP-43 detection in native skin biopsies and corresponding CNS tissues in SALS patients. Immunohistochemistry analysis, using anti-TDP-43 antibody, revealed the presence of TDP-43 cytoplasmic accumulation in both native skin biopsies (b) and post-mortem (c) spinal cord tissues collected from SALS patients. Such TDP-43 cytoplasmic accumulation was not detected in control individuals (a).
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Fig5: Cytoplasmic TDP-43 detection in native skin biopsies and corresponding CNS tissues in SALS patients. Immunohistochemistry analysis, using anti-TDP-43 antibody, revealed the presence of TDP-43 cytoplasmic accumulation in both native skin biopsies (b) and post-mortem (c) spinal cord tissues collected from SALS patients. Such TDP-43 cytoplasmic accumulation was not detected in control individuals (a).

Mentions: To further confirm our results, we undertook immunohistochemistry colorations, generally the method of choice in hospital pathological departments, on native skin biopsies collected from the corresponding ALS patients as well as on post-mortem spinal cord tissues when available. The IHC analysis confirmed the presence of cytoplasmic TDP-43 skein-like inclusions in the fibroblasts of the native skin biopsies taken from living SALS patients (Figure 5; Additional file 7: Figure S5). Moreover, round TDP-43 cytoplasmic inclusions in the dentate gyrus’s granular layer as well as skein-like TDP-43 cytoplasmic positive inclusions in neurons present in the ventral horn of the spinal cord were also detected by the neuropathologists after formal autopsies (Figure 5).Figure 5


Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients.

Paré B, Touzel-Deschênes L, Lamontagne R, Lamarre MS, Scott FD, Khuong HT, Dion PA, Bouchard JP, Gould P, Rouleau GA, Dupré N, Berthod F, Gros-Louis F - Acta Neuropathol Commun (2015)

Cytoplasmic TDP-43 detection in native skin biopsies and corresponding CNS tissues in SALS patients. Immunohistochemistry analysis, using anti-TDP-43 antibody, revealed the presence of TDP-43 cytoplasmic accumulation in both native skin biopsies (b) and post-mortem (c) spinal cord tissues collected from SALS patients. Such TDP-43 cytoplasmic accumulation was not detected in control individuals (a).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359444&req=5

Fig5: Cytoplasmic TDP-43 detection in native skin biopsies and corresponding CNS tissues in SALS patients. Immunohistochemistry analysis, using anti-TDP-43 antibody, revealed the presence of TDP-43 cytoplasmic accumulation in both native skin biopsies (b) and post-mortem (c) spinal cord tissues collected from SALS patients. Such TDP-43 cytoplasmic accumulation was not detected in control individuals (a).
Mentions: To further confirm our results, we undertook immunohistochemistry colorations, generally the method of choice in hospital pathological departments, on native skin biopsies collected from the corresponding ALS patients as well as on post-mortem spinal cord tissues when available. The IHC analysis confirmed the presence of cytoplasmic TDP-43 skein-like inclusions in the fibroblasts of the native skin biopsies taken from living SALS patients (Figure 5; Additional file 7: Figure S5). Moreover, round TDP-43 cytoplasmic inclusions in the dentate gyrus’s granular layer as well as skein-like TDP-43 cytoplasmic positive inclusions in neurons present in the ventral horn of the spinal cord were also detected by the neuropathologists after formal autopsies (Figure 5).Figure 5

Bottom Line: As a result, the identification and development of disease-modifying therapies is difficult.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.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.

View Article: PubMed Central - PubMed

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 physiophatological mechanisms underlying this disease, to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early diagnosis and disease monitoring.

Show MeSH
Related in: MedlinePlus