Microglial Activation in the Pathogenesis of Huntington’s Disease

Abstract

Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expanded CAG trinucleotide repeats (>36) in exon 1 of HTT gene that encodes huntingtin protein. Although HD is characterized by a predominant loss of neurons in the striatum and cortex, previous studies point to a critical role of aberrant accumulation of mutant huntingtin in microglia that contributes to the progressive neurodegeneration in HD, through both cell-autonomous and non-cell-autonomous mechanisms. Microglia are resident immune cells in the central nervous system (CNS), which function to surveil the microenvironment at a quiescent state. In response to various pro-inflammatory stimuli, microglia become activated and undergo two separate phases (M1 and M2 phenotype), which release pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), anti-inflammatory cytokines, and growth factors (TGF-β, CD206, and Arg1), respectively. Immunoregulation by microglial activation could be either neurotoxic or neuroprotective. In this review, we summarized current understanding about microglial activation in the pathogenesis and progression of HD, with a primary focus of M1 and M2 phenotype of activated microglia and their corresponding signaling pathways.

MiR-124 and the Underlying Therapeutic Promise of Neurodegenerative Disorders

“…HD is no exception, as there is increasing evidence that activated microglia can be detected in the brains of HD carriers and the post-mortem HD patients. In particular, elevated inflammatory cytokines are detected in the CNS and plasma of HD patients (Politis et al, 2015;Yang et al, 2017). Neuronal expression of mutant HTT and intrinsic mutant protein may be responsible for activating microglia.…”

“…Neuronal expression of mutant HTT and intrinsic mutant protein may be responsible for activating microglia. Activated microglia are present in a continuum of two functional states of polarization (M1 and M2 phenotypes) in which they extend damage to neighboring cells and then release different inflammatory factors (Yang et al, 2017). These inflammatory factors include pro-inflammatory cytokines (TNF-a and IL-1 b), chemokines (CCL2), MMP-9, IL-10, TGF-b, vascular endothelial growth factor, and insulin-like growth factor-1, which further activate the microglia activation signaling pathway in HD (Chhor et al, 2013;Cianciulli et al, 2015;Franco and Fernandez-Suarez, 2015;Orihuela et al, 2016).…”

Enforced microglial depletion and repopulation as a promising strategy for the treatment of neurological disorders

“…Apart from beneficial roles in the development of CNS, microglia can be widely involved in various types of neurological disorders, including stroke (Guruswamy & ElAli, ; Kronenberg et al, ), multiple sclerosis (MS) (Bogie, Stinissen, & Hendriks, ; Luo et al, ), AD (Hansen, Hanson, & Sheng, ; Sarlus & Heneka, ), PD (Subramaniam & Federoff, ), sleep disorders (Nadjar, Wigren, & Tremblay, ), amyotrophic lateral sclerosis (ALS) (Geloso et al, ; Liu & Wang, ), Huntington's disease (H. M. Yang, Yang, Huang, Tang, & Guo, ), epilepsy (Eyo, Murugan, & Wu, ; Zhao, Liao, et al, ), gliomas (Hambardzumyan, Gutmann, & Kettenmann, ; Schiffer, Mellai, Bovio, & Annovazzi, ), Prion diseases (Aguzzi & Zhu, ; Obst, Simon, Mancuso, & Gomez‐Nicola, ), psychiatric disorders (Mondelli, Vernon, Turkheimer, Dazzan, & Pariante, ; Prinz & Priller, ; Setiawan et al, ; Singhal & Baune, ), neuropathic pain (Inoue & Tsuda, ; Peng et al, ), adrenomyeloneuropathy (Gong et al, ), and traumatic brain injury (Donat, Scott, Gentleman, & Sastre, ). In general, microglia can be rapidly activated depending upon different stimulatory contexts and environmental changes through diverse molecular and cellular programs, subsequently transforming into the activated state and enhancing the expression of the Toll‐like receptors which sensitively bind microbial structures (Arcuri et al, ).…”

Microglial physiological properties and interactions with synapses are altered at presymptomatic stages in a mouse model of Huntington’s disease pathology

“…Microglia are responsible for normal synaptic pruning and maintenance and have been implicated in a number of disease states associated with synaptic loss and neurodegeneration [20,21]. Recently, microglia have begun to be studied in the specific context of HD [22]. Morphologically reactive microglia (defined by large, amoeboid-like cell bodies with short or absent processes) have been identified in postmortem samples of cerebral cortex and striatum from HD patients, as well as in the striatum of mouse models of HD [23,24].…”