Faltering Glial Cell Activities in the Development of Parkinson's Disease

Glial cells in the brain are a class of immune cell responsible for a wide range of supporting activities necessary to brain function, a great deal more than merely tackling pathogens and cleaning up metabolic waste. It is the ingestion and breaking down of metabolic waste in the brain, a process called phagocytosis, that is the focus of this open access paper, however. Neurodegenerative conditions, such as Parkinson's disease in this case, are largely characterized by the presence of solid deposits of misfolded or otherwise altered proteins. The capacity of glial cells to carry out phagocytosis of these protein aggregates is disrupted with advancing age, particularly by rising levels of chronic inflammation. It is suspected that this loss of function is a significant contribution to the progression of neurodegeneration. Recent studies showing that clearance of senescent glial cells produces significant benefits in animal models of neurodegeneration supports this line of thinking, but there is still much work to be accomplished in this area of study.

The clinical symptoms of Parkinson's disease (PD) reflect the underlying systemic neurodegeneration and protein deposition. A common denominator of both inherited and sporadic forms of PD is the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta projecting to the putamen that control voluntary movements. Additionally, proteinaceous inclusions mainly composed by the protein α-synuclein (α-syn) are located in the perikarya (Lewy Bodies, LBs) and within the cell processes (Lewy neurites, LNs) of the surviving nerve cells.

Although less often discussed than neuronal pathology, α-syn-containing inclusions in astrocytes have been repeatedly detected in the substantia nigra, cerebral cortex and other brain regions in idiopathic PD samples. The density of α-syn immunoreactive astrocytes parallels the occurrence of LNs and LBs in neurons. Neuronal loss and the presence of cytoplasmic inclusions in neuronal and non-neuronal cells are also accompanied by reactive changes of astrocytes and microglia referred to as gliosis. Microglia as well as astrocytes are inflammatory cells that express immune-associated molecules including the major histocompatibility complex (MHC) class II, pro-inflammatory cytokines, and inducible oxide synthase (iNOS). Moreover, astrocytes become hypertrophic and accumulate the intermediate filament protein, glial fibrillary acidic protein (GFAP).

Although reactive glial cells and the upregulation of cytokines was found in the brains and cerebrospinal fluid of patients with PD, the role of neuroinflammation in the pathogenesis of PD is still undetermined. Neuroinflammation in PD has long been considered a downstream response to neuronal damage. However, alteration of glial physiological functions are emerging as causally linked to brain diseases. In the healthy brain, astrocytes maintain ion homeostasis of the microenvironment, provide structural and metabolic support, regulate synaptic transmission, water transport, and blood flow. Additionally, microglia continuously extend and retract their process to interact with neurons and other types of glial cells, including astrocytes.

Microglial phagocytosis (alongside other mechanisms, such as synaptic stripping and "trogocytosis") plays an important role in the engulfment of synaptic elements. Recent studies also revealed that astrocytes contribute to phagocytic clearance in a similar manner during normal physiological conditions and there is abundant evidence that microglia and astrocytes communicate with each other. It was further proposed that astrocytes can ingest aggregated proteins from the extracellular environment, suggesting that astrocytes keep, in coordination with microglia, the brain clean. Since the elimination of unwanted and potentially harmful matter is crucial for central nervous system (CNS) function, dysregulation of glial phagocytosis and degradation might have a key role in PD pathogenesis.

Link: https://doi.org/10.1186/s13024-019-0314-8

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