Significance of aberrant glial cell phenotypes in pathophysiology of amyotrophic lateral sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a paradigmatic neurodegenerative disease, characterized by progressive paralysis of skeletal muscles associated with motor neuron degeneration. It is well-established that glial cells play a key role in ALS pathogenesis. In transgenic rodent models for familial ALS reactive astrocytes, microglia and oligodendrocyte precursors accumulate in the degenerating spinal cord and appear to contribute to primary motor neuron death through a non-cell autonomous pathogenic mechanism. Furthermore in rats expressing the ALS-linked SOD1 mutation, rapid spread of paralysis coincides with emergence of neurotoxic and proliferating aberrant glia cells with an astrocyte-like phenotype (AbA cells) that are found surrounding damaged motor neurons. AbAs simultaneously express astrocytic markers GFAP, S100β and Connexin-43 along with microglial markers Iba-1, CD11b and CD163. Studies with cell cultures have shown that AbAs originate from inflammatory microglial cells that undergo phenotypic transition. Because AbAs appear only after paralysis onset and exponentially increase in parallel with disease progression, they appear to actively contribute to ALS progression. While several reviews have been published on the pathogenic role of glial cells in ALS, this review focuses on emergence and pro-inflammatory activity of AbAs as part of an increasingly complex neurodegenerative microenvironment during ALS disease development.

Evidence for mast cells contributing to neuromuscular pathology in an inherited model of ALS

“…The cause of ALS remains largely unknown, and there exists an urgent unmet medical need for drugs that can stop or delay disease progression. In the CNS, ALS is typically accompanied by neuroinflammation involving the emergence of reactive microglia, astrocytes, and aberrant glial phenotypes (3)(4)(5). Evidence also shows activation of circulating immune cells (6), as well as immune cell infiltration of the ALS-degenerating peripheral nerves containing motor axons (7)(8)(9)(10).…”

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

“…Damage neurons express a large variety of inflammatory mediators such as CSF1, TGF-β, IFNγ, and Fas/FasL, with the potential to elicit a localized inflammatory response [76-80]. Innate and adaptive immune responses underlie neuroinflammation, involving the complex participation of microglia, as the resident immune cell of the CNS as well as astrocytes and oligodendrocytes, which actively interact with other immune cells including T cells, monocytes, and mast cells [81-86]. …”

“…Among them, ALS is a paradigmatic disease where inflammation develops along the motor pathway, into both the CNS and the peripheral nervous system (PNS) [81, 93, 94]. Moreover, therapeutic compounds targeting inflammation are currently being tested in a clinical trial with the aim to reduce the upper and lower motor neuron degeneration in ALS, thus delaying progressive muscle weakness [95-97].…”

“…Based upon these observations, Trias et al[129] investigated whether ALS progression might be ameliorated by masitinib, a drug that potently targets aberrant glial cells through the inhibition of the tyrosine kinase receptor CSF-1R. ALS rats treated with masitinib after paralysis onset displayed decreased inflammation in the CNS and PNS [129], and in parallel the treatment prevented motor neuron loss and denervation of neuromuscular junctions [81, 129]. …”

“…These cells are known to permeate the BBB in specific regions and actively interact with the degenerative cellular microenvironment surrounding motor neurons and motor axons [81, 131, 133, 134]. It is also possible that chronic neuroinflammation restricted to the CNS can extend to skeletal muscles and then to other organs, becoming a systemic inflammation [135, 136].…”