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

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.

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP‐43 subcellular distribution

“…However, neuronal aggregates negative for TDP‐43, but enriched in other proteins (such as p62), are considered pathognomonic for this group of patients . Furthermore, TDP‐43 dysfunctions may or may not characterize cell lineages with mutant C9ORF72 . Herein, of the mutant C9ORF72 patients recruited, cytoplasmic accumulation of TDP‐43 was manifest in monocytes in all and also in lymphocytes only in one.…”

TDP-43 regulates endogenous retrovirus-K viral protein accumulation

“…Page 5 of 35 Nardo et al, 2011;Noto et al, 2011;Pare et al, 2015). Only 5-10% of familial and 1% of sporadic ALS cases carry TDP-43 mutations (Lattante et al, 2012;Millecamps et al, 2010), yet wild-type TDP-43 is incorrectly processed in the majority of patients with ALS (Janssens and Van Broeckhoven, 2013).…”

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…In addition, in TES reconstructed from asymptomatic C9ORF72 carriers of GGGGCC repeat expansion, cytoplasmic TDP‐43 inclusions were detected. Importantly, the same authors demonstrated with immunohistochemistry that TDP‐43 cytoplasmic inclusions are present in native skin biopsies (Paré et al., ). Also, TDP‐43 immunohistochemical signal intensity is higher in the skin of ALS patients compared with control patients (Suzuki et al., ).…”

“…The ALS‐TES contained both fibroblasts and keratinocytes. ALS‐TES reveals stratum corneum detachment, abnormal dermo–epidermal junction and collagen misorganization, as opposed to TES from normal individuals (Paré et al., ). In the ALS‐TES, TDP‐43 aggregates are observed, indicating that these aggregates can be detected outside the nervous system.…”