Inflammation and heterogeneity in synucleinopathies

Abstract

Neurodegenerative diseases represent a huge healthcare challenge which is predicted to increase with an aging population. Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), present complex challenges in understanding their onset and progression. They are characterized by the abnormal aggregation of α-synuclein in the brain leading to neurodegeneration. Accumulating evidence supports the existence of distinct subtypes based on the site of α-synuclein aggregation initiation, genetics, and, more recently, neuroinflammation. Mediated by both central nervous system-resident cells, peripheral immune cells, and gut dysbiosis, neuroinflammation appears as a key process in the onset and progression of neuronal loss. Sex-based differences add another layer of complexity to synucleinopathies, influencing disease prevalence - with a known higher incidence of PD in males compared to females - as well as phenotype and immune responses. Biological sex affects neuroinflammatory pathways and the immune response, suggesting the need for sex-specific therapeutic strategies and biomarker identification. Here, we review the heterogeneity of synucleinopathies, describing the etiology, the mechanisms by which the inflammatory processes contribute to the pathology, and the consideration of sex-based differences to highlight the need for personalized therapeutics.

Keywords: Parkinson’s disease; dementia with Lewy bodies; immunity; multiple system atrophy; neurodegeneration; neuroinflammation; sex-based differences.

Figure 1

Brain resident cells in synucleinopathies and neuroinflammation. In synucleinopathies, α-syn abnormally accumulates in Lewy bodies (LBs) or Lewy neurites (LNs) for Lewy body diseases DLB and PD or in glial cytoplasmic inclusions (GCIs) for MSA. α-syn aggregates are released by damaged neurons and oligodendrocytes and recognized by resident astrocytes and microglia via Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4). Activation of TLRs by α-syn leads to the differentiation of activated pro-inflammatory A1 astrocytes and activated microglia. Through a pro-inflammatory signaling cascade mediated by NFκB and p38 MAPK, A1 astrocytes and activated microglia express several chemokines, cytokines, neurotoxins, reactive oxygen species (ROS), and nitric oxide (NO). This pro-inflammatory milieu contributes to neuronal loss. Additionally, with the action of activated microglia phagocytizing astrocytes, the integrity of the blood-brain barrier (BBB) is compromised, allowing the invasion of peripheral mediators and immune cells. Among them, T cells can be activated via the recognition of a specific major histocompatibility complex (MHC)-peptide presented by astrocytes, microglia, or infiltrating monocytes, ultimately leading to neuronal loss. α-syn, α-synuclein; DLB, dementia with Lewy bodies; PD, Parkinson’s disease; MSA, multiple sclerosis atrophy; LBs, Lewy bodies; LNs, Lewy neurites; GCIs, Glial cytoplasmic inclusions; TLRs (2-4), toll-like receptors; ROS, reactive oxygen species; NO, nitric oxide; BBB, blood-brain-barrier.

Figure 2

Adaptative immune cells contribute to neurodegeneration in synucleinopathies. Pathogenic α-syn aggregates in neurons (PD, DLB) or in oligodendrocytes (MSA) are released and captured by antigen-presenting cells (APCs) such as microglia, astrocytes, and infiltrating monocytes. These APCs process and present α-syn peptides on their major histocompatibility complex (MHC) molecules. Alternatively, neurons can directly present α-syn peptides on their MHC class I molecule. Upon TCR triggering, CD8+ T cells secrete IFNγ or cytotoxic granules (Granzymes, perforin), inducing neuronal death. B cells recognize α-syn through their BCR and, with the aid of T helper cells, mature into plasma cells producing α-syn autoantibodies, potentially contributing to neuronal damage. B cells also release pro-inflammatory cytokines such as TNFα and IL-6, promoting T cell differentiation into Th1 and Th17 cells, thereby contributing to T cell-mediated inflammation. Following MHC-II/TCR interaction, CD4+ T cells further differentiate into Th17 cells, producing IL-17 that directly promotes neuronal loss via neuronal IL-17 receptors. CD4+ T cells can also differentiate into Th1 or Th2 cells, secreting IFN-γ and IL-5, respectively, further activating CNS-resident microglia and astrocytes, thereby promoting a deleterious inflammatory environment. Regulatory T cells in synucleinopathies exhibit impaired suppressive functions, failing to counteract T cell-mediated inflammation. Lastly, the BBB is compromised in patients, allowing the migration of immune cells and mediators into the brain, perpetuating the pro-inflammatory loop. α-syn, α-synuclein; DLB, dementia with Lewy bodies; PD, Parkinson’s disease; MSA, multiple sclerosis atrophy; MHCI-II, major histocompatibility complexes I-II; TCR, T-cell receptor; APCs, antigen-presenting cells; BCR, B-cell receptor; BBB, Blood brain barrier; CNS, central nervous system.