Rapidly progressive amyotrophic lateral sclerosis is associated with microglial reactivity and small heat shock protein expression in reactive astrocytes

Abstract

Aims Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by progressive loss of motor neurons, muscle weakness, spasticity, paralysis and death usually within 2–5 years of onset. Neuroinflammation is a hallmark of ALS pathology characterized by activation of glial cells, which respond by upregulating small heat shock proteins (HSPBs), but the exact underlying pathological mechanisms are still largely unknown. Here, we investigated the association between ALS disease duration, lower motor neuron loss, TARDNA‐binding protein 43 (TDP‐43) pathology, neuroinflammation and HSPB expression. Methods With immunohistochemistry, we examined HSPB1, HSPB5, HSPB6, HSPB8 and HSP16.2 expression in cervical, thoracic and sacral spinal cord regions in 12 ALS cases, seven with short disease duration (SDD), five with moderate disease duration (MDD), and ten age‐matched controls. Expression was quantified using ImageJ to examine HSP expression, motor neuron numbers, microglial and astrocyte density and phosphorylated TDP‐43 (pTDP‐43+) inclusions. Results SDD was associated with elevated HSPB5 and 8 expression in lateral tract astrocytes, while HSP16.2 expression was increased in astrocytes in MDD cases. SDD cases had higher numbers of motor neurons and microglial activation than MDD cases, but similar levels of motor neurons with pTDP‐43+ inclusions. Conclusions Increased expression of several HSPBs in lateral column astrocytes suggests that astrocytes play a role in the pathogenesis of ALS. SDD is associated with increased microgliosis, HSPB5 and 8 expression in astrocytes, and only minor changes in motor neuron loss. This suggests that the interaction between motor neurons, microglia and astrocytes determines neuronal fate and functional decline in ALS.

Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration

“…Microglial activation is consistently detected in the motor cortex however one study also detected an increase in the dorsolateral prefrontal cortex and thalamus (Turner et al, 2004). Interestingly, microgliosis appears to associate with disease severity (Turner et al, 2004; Brettschneider et al, 2012; Zürcher et al, 2015), with a recent study suggesting microgliosis is specifically associated with rapid disease progression (Gorter et al, 2018). Taking a data-driven approach, another recent work uncovered networks of genes that associate with motor neuron pathology in human ALS brain.…”

“…Small heat shock proteins (HSPBs) are important chaperones that reduce protein misfolding and aid in misfolded protein degradation. A recent study has found that in human ALS spinal cord, rapidly progressing disease was associated with increased HSPB5 and HSPB8 in astrocytes (Gorter et al, 2018). Furthermore, a recent rat model with restricted mutant human TDP-43 (M337V) expression in astrocytes, displayed a progressive paralysis due to loss of motor neurons in the spinal cord (Tong et al, 2013).…”

The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death

“…It has been shown that, during disease manifestations and at the end stage of disease, HSPB8 is highly expressed in the spinal cord of the SOD1-G93A ALS mouse model and in spinal cord specimens of ALS patients (Anagnostou et al, 2010; Crippa et al, 2010). Moreover, HSPB8 was found upregulated in the lateral tract astrocytes of patients with short disease duration (Gorter et al, 2018). In the SOD1-G93A ALS mouse model, the high levels of HSPB8 are confined specifically in anterior horn spinal cord motoneurons that survive at the end stage of disease (Crippa et al, 2010).…”

Metabolic Regulation of Glial Phenotypes: Implications in Neuron–Glia Interactions and Neurological Disorders

“…The activated microglial and reactive astrocytes also constitute an important element of ALS, which is a lateonset neurodegenerative disease, involving the impaired survival of upper and lower motor neurons (Geser et al, 2008;Yamanaka et al, 2008;Gorter et al, 2019). Neurotoxic glial cells surrounding the motor neurons play a crucial role in ALS.…”