Abstract
The role of neuroinflammation has been increasingly recognized in the field of neurodegenerative diseases. Many studies focusing on the glial cells involved in the inflammatory responses of the brain, namely microglia and astroglia, have over the years pointed out the dynamic and changing behavior of these cells, accompanied by different morphologies and activation forms. This is particularly evident in diseased conditions, where glia react to any shift from homeostasis, acquiring different phenotypes. Particularly for microglia, it has soon become clear that such phenotypes are multiple, as multiple are the functions related to them. Several approaches have over time revealed different facets of microglial phenotypic diversity, and advanced genetic analyses, in recent years, have added new insights into microglial heterogeneity, opening novel scenarios that researchers have just started to explore. Among neurodegenerative diseases, an important section is represented by alpha-synucleinopathies. Here alpha-synuclein accumulates abnormally in the brain and, depending on its pattern of distribution, leads to the development of different clinical conditions. Also for these proteinopathies, neuroinflammation and glial activation have been identified as constant and crucial factors during disease development. In the present review we will address the current literature about glial phenotypic changes with respect to alpha-synucleinopathies, as well as consider the pathophysiological and therapeutic implications of such a dynamic cellular behavior.
Highlights
Alpha-synucleinopathies are a family of neurodegenerative disorders characterized by the misfolding and accumulation in the brain of alpha-synuclein, a 140-amino-acid protein, encoded by the SNCA gene
Whereas in Parkinson’s disease (PD) and dementia with Lewi bodies (DLB) alphasynuclein forms filamentous aggregates in neurons, in form of Lewy bodies and Lewy neurites (Spillantini et al, 1997, 1998a), multiple system atrophy (MSA) is mainly characterized by oligodendrocytic inclusions of the protein, called glial cytoplasmic inclusions (GCIs), representing the hallmark of the disease
In 2017 Liddelow and coworkers introduced the distinction between “A1” and “A2” astrocytes; they defined as A1 those with a detrimental function, showing upregulation of genes involved in the classical complement cascade, and A2 those with a beneficial effect, mainly upregulating genes encoding for neurotrophic factors
Summary
Many studies focusing on the glial cells involved in the inflammatory responses of the brain, namely microglia and astroglia, have over the years pointed out the dynamic and changing behavior of these cells, accompanied by different morphologies and activation forms. This is evident in diseased conditions, where glia react to any shift from homeostasis, acquiring different phenotypes. Alpha-synuclein accumulates abnormally in the brain and, depending on its pattern of distribution, leads to the development of different clinical conditions For these proteinopathies, neuroinflammation and glial activation have been identified as constant and crucial factors during disease development.
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