Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis

Abstract

Astrocytes have emerged as critical elements for the maintenance and function of the central nervous system. The expression on their cell membrane of RAGE and TLR4 receptors makes astrocytes susceptible to High-mobility group box 1 (HMGB1), a nuclear protein typically released in the extracellular milieu by living cells experiencing physiological stress conditions or by damaged cells. Here, we show that the interaction of HMGB1 with normal spinal cord astrocytes induces the astrocytic production of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Multiple investigations suggest a role for HMGB1 in amyotrophic lateral sclerosis (ALS). Yet, no mechanistic information on the implication of HMGB1 signaling in this disorder is currently available. We demonstrate that non-transgenic and transgenic SOD1WT spinal motor neurons exhibit only a basal nucleus-to-cytoplasm shuttling of the HMGB1 protein. Conversely, in SOD1G93A ALS mouse spinal cords, HMGB1 significantly translocates from the nucleus to the cytoplasm of motor neurons, thereby suggesting that it may be eventually released in the extracellular environment during the progression of the disease. We postulate that extracellular HMGB1 can paracrinally interact with the neighboring astrocytes in an attempt to counteract the neurodegenerative process. Yet, at variance with normal cells, SOD1G93A-expressing astrocytes show impaired capacity to raise BDNF and GDNF levels upon HMGB1 stimulation. Our data suggest that HMGB1 have a potential to promote neuroprotective actions by healthy astrocytes. However, this neurotrophic response is disrupted in ALS astrocytes. This indicates that diseased astroglial cells may exacerbate motor neuron degeneration in ALS because of the loss of their neurosupportive functions.

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders

“…In murine models of ALS, it was initially noted that preventing NF-kB activation in astrocytes did not ameliorate the pathological phenotype [173,174] or it was even detrimental [175]. In line with these observations, we demonstrated that activating NF-kB in astrocytes can lead to the production of growth factors that are known to support neuronal survival, namely brain-derived neurotrophic factor (BDNF) and GDNF [176]. However, pharmacological treatment with the NF-kB inhibitor Withaferin A ameliorated the phenotype of several models of ALS [177][178][179].…”

Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1G93A mouse model of amyotrophic lateral sclerosis

“…Our results indicate therefore that HMGB1 activation of TLR2, TLR4 and RAGE in SOD1 G93A mice may be compensated for by other endogenous ligands, which may explain the lack of efficacy on survival with anti-HMGB1 antibody treatment. Furthermore, others have also suggested that astrocytic HMGB1 signalling in ALS could be neuroprotective via release of neurotrophic factors such as brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor [48].…”

Anti-High Mobility Group Box-1 Monoclonal Antibody Attenuates Seizure-Induced Cognitive Decline by Suppressing Neuroinflammation in an Adult Zebrafish Model

“…Furthermore, HMGB1 possess two DNA-binding terminals (termed A and B-boxes) and a negatively charged C-terminal tail that contains a recurring chain of 30 glutamic and aspartic acids ( Aucott et al, 2018 ; Paudel et al, 2019a ). In recent days, HMGB1 has been extensively explored in several HMGB1 mediated neurological pathologies including Epileptogenesis ( Maroso et al, 2010 ; Paudel et al, 2019b ), Parkinson’s disease (PD) ( Gao et al, 2011 ; Angelopoulou et al, 2018 ), Alzheimer’s disease (AD) ( Takata et al, 2004 ; Paudel et al, 2020a ), Multiple sclerosis (MS) ( Andersson et al, 2008 ; Paudel et al, 2019a ) and ALS ( Brambilla et al, 2018 ; Paudel et al, 2020c ) and Brain injuries ( Okuma et al, 2012 ; Paudel et al, 2020b ).…”