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

Frontiers in Neurology, 2017 · DOI: 10.3389/fneur.2017.00669 · Published: December 15, 2017

Simple Explanation

Amyotrophic lateral sclerosis (ALS) is a fatal disease, and inflammatory and fibrotic processes may contribute to the heterogeneity and dynamics of ALS. The TGF-β system is involved in essential physiological processes and regulates immunity and fibrosis, both affecting neurogenesis and neurodegeneration. This study assessed the activation state of the TGF-β system within the periphery and the central nervous system, and a potential influence upon neuronal stem cell activity, immune activation, and fibrosis.

Study Duration

Not specified

Participants

37 ALS patients and 11 healthy controls (serum samples); 18 ALS patients and 17 healthy controls (postmortem tissue)

Evidence Level

Not specified

Key Findings

1
ALS patients exhibit enhanced circulating TGF-β1 serum levels.
2
ALS patients exhibit an enhanced peripheral proinflammatory immune profile with increased concentrations of MCP-1, MCP-4, TNFα, TNFβ, MIP-1β, IL-15, IP-10, and TARC in serum.
3
ALS patients exhibit a shift toward a neurotoxic and destructive immune profile at the final disease stage in postmortem tissue.

Research Summary

This study provides evidence from human data that an enhanced TGF-β system activity may critically mediate the imbalance of neuroregenerative and neurodegenerative processes in ALS. The analysis of patient sera and postmortem SC tissue samples suggests an enhanced “neurodestructive” immune profile in ALS patients compared to healthy controls, reflected by increased expression of proinflammatory versus unchanged or reduced levels of anti-inflammatory cytokines. The specific immunological, neurogenic, and fibrotic alterations described might indicate potential “hot spots” of ALS disease burden, reflecting initial local foci that continuously expand to adjacent areas during different stages of disease burden, potentially mediating and driving ALS progression.

Practical Implications

Therapeutic Target

The TGF-β system may represent a promising target for ALS treatment, particularly in modulating the balance between neuroregeneration and neurodegeneration.

Diagnostic Markers

Circulating TGF-β1 levels and proinflammatory immune markers in serum may serve as potential biomarkers for ALS diagnosis or disease progression.

Stem Cell Activity Modulation

Targeting TGF-β signaling may help to restore or enhance neuronal stem cell activity in ALS patients, potentially improving neuronal compensation and slowing disease progression.

Study Limitations

1
Seemingly marginal differences of TGF-β ligand levels within sera and CNS tissue lysates between ALS patients and healthy controls.
2
Lack of active TGF-β assessment on the protein level may limit full comprehension of TGF-β system.
3
The authors are aware that adult human neurogenesis was exclusively shown within the SGZ and the SVZ so far.

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