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

R P Gorter,C Mijnsbergen,J M Van Noort,S Amor,E Aronica,J C De Jonge,E Nutma,J Stephenson,J A M Belien,M.‐C Jahreiβ,W Baron,J Anink

doi:10.1111/nan.12525

Abstract

AimsAmyotrophic 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.MethodsWith 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.ResultsSDD 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.ConclusionsIncreased 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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder in which motor neurons in the motor cortex, brainstem and spinal cord degenerate, leading to spasticity, muscle weakness and atrophy [1]
We show that HSPB expression by motor neurons and astrocytes is altered in ALS and that HSPB expression is associated with ALS disease duration
Spinal cords of ALS patients (SDD and moderate disease duration (MDD)) and nonneurological controls were characterized based on motor neuron counts (Figure 1A), ventral horn surface area (Figure 1B), TARDNA-binding protein 43 (TDP-43) pathology (Figure 1C,D) and HLADR reactivity (Figure 1L,P)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder in which motor neurons in the motor cortex, brainstem and spinal cord degenerate, leading to spasticity, muscle weakness and atrophy [1]. The majority of ALS cases are sporadic, genetic mutations are associated with familial forms of the disease in 5–10% of cases [1]. All these mutations affect genes involved in protein homoeostasis (proteostasis) [4]. In response to increased or dysfunctional proteostasis, cells upregulate heat shock proteins (HSPs) to protect against cellular damage that accumulates during pathological conditions [6]. Given the strong association between protein aggregation, glial activation and neurodegeneration, the expression and role of HSPs in the central nervous system (CNS) is attracting attention in many neurodegenerative disorders [8], especially as studies show that HSPs can potentially act as neuroprotective agents [9]. Several HSPs are constitutively expressed in the CNS while others are only observed in pathological conditions such as in Alzheimer’s disease, Parkinson’s disease, Alexander’s disease, multiple sclerosis and X-linked adrenoleucodystrophy [11,12,13,14,15]

Methods

Results

Conclusion