The TGF-β System As a Potential Pathogenic Player in Disease Modulation of Amyotrophic Lateral Sclerosis

Frontiers in Neurology

Dietmar R. Thal¹  Sabine Iberl²  Andreas Hermann³  Susanne Petri⁴  Tim-Henrik Bruun⁵  Eva Zitzelsperger⁵  Ulrich Bogdahn⁵  Rosmarie Heydn⁵  Siw Johannesen⁵  Sebastian Peters⁵  Sabrina Kuespert⁵  Jochen H. Weishaupt⁶  Ludwig Aigner⁷ 

[1] Department for Neuroscience, Laboratory for Neuropathology, University of Leuven, Leuven, Belgium;Department of Hematology, University Hospital Regensburg, Regensburg, Germany;Department of Neurology, Technische Universität Dresden and German Center for Neurodegenerative Diseases (DZNE), Research Site Dresden, Dresden, Germany;Department of Neurology, University Hospital MHH, Hannover, Germany;Department of Neurology, University Hospital Regensburg, Regensburg, Germany;Department of Neurology, University Hospital Ulm, Ulm, Germany;Institute of Molecular Regenerative Medicine, Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria;

关键词: amyotrophic lateral sclerosis;    TGF-β;    immunity;    adult neurogenic niche;    fibrosis;   

DOI  :  10.3389/fneur.2017.00669

来源: DOAJ

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) represents a fatal orphan disease with high unmet medical need, and a life time risk of approx. 1/400 persons per population. Based on increasing knowledge on pathophysiology including genetic and molecular changes, epigenetics, and immune dysfunction, inflammatory as well as fibrotic processes may contribute to the heterogeneity and dynamics of ALS. Animal and human studies indicate dysregulations of the TGF-β system as a common feature of neurodegenerative disorders in general and ALS in particular. The TGF-β system is involved in different essential developmental and physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. Therefore, it has emerged as a potential therapeutic target for ALS: a persistent altered TGF-β system might promote disease progression by inducing an imbalance of neurogenesis and neurodegeneration. The current study assessed the activation state of the TGF-β system within the periphery/in life disease stage (serum samples) and a late stage of disease (central nervous system tissue samples), and a potential influence upon neuronal stem cell (NSC) activity, immune activation, and fibrosis. An upregulated TGF-β system was suggested with significantly increased TGF-β1 protein serum levels, enhanced TGF-β2 mRNA and protein levels, and a strong trend toward an increased TGF-β1 protein expression within the spinal cord (SC). Stem cell activity appeared diminished, reflected by reduced mRNA expression of NSC markers Musashi-1 and Nestin within SC—paralleled by enhanced protein contents of Musashi-1. Doublecortin mRNA and protein expression was reduced, suggesting an arrested neurogenesis at late stage ALS. Chemokine/cytokine analyses suggest a shift from a neuroprotective toward a more neurotoxic immune response: anti-inflammatory chemokines/cytokines were unchanged or reduced, expression of proinflammatory chemokines/cytokines were enhanced in ALS sera and SC postmortem tissue. Finally, we observed upregulated mRNA and protein expression for fibronectin in motor cortex of ALS patients which might suggest increased fibrotic changes. These data suggest that there is an upregulated TGF-β system in specific tissues in ALS that might lead to a “neurotoxic” immune response, promoting disease progression and neurodegeneration. The TGF-β system therefore may represent a promising target in treatment of ALS patients.

【 授权许可】

Unknown