How do microglia and astrocytes contribute to neurodegeneration in PD?

Immune responses play a role in the pathophysiology of Parkinson’s disease (PD),¹ said Professor David Sulzer, New York, NY. Evidence for this role has been provided by a number of studies:

Microglia are activated by extracellular neuromelanin

• leucine-rich repeat kinase 2 (LRRK2) regulates immune cell responses in the brain and LRRK2 mutation is a risk for PD²
• genome-wide association studies suggest the involvement of antigen-presenting cells³ such as microglia
• microglia are activated by extracellular neuromelanin leading to the production of pro-inflammatory factors and neurodegeneration⁴
• neuronal major histocompatibility complex class I (MHC-I) can trigger an antigenic response, and catecholamine neurons may be susceptible to T-cell-mediated cytotoxic attack⁵

α-synuclein-specific T cell responses are highest shortly after a diagnosis of motor PD

• α-synuclein-specific T cell responses have been detected before a diagnosis of motor PD and are highest shortly after the diagnosis, but then decline⁶
• increased T-helper cell 17 (Th17) frequencies have been found in the blood of patients with PD, increased numbers of T cells have been detected in post-mortem PD brain, and co-culture of induced pluripotent stem cell (iPSC)-derived PD midbrain neurons with T cells or the addition of interleukin-17 (IL-17) leads to increased neuronal death driven by upregulation of the IL-17 receptor (IL-17R) and NFkB activation⁷

Astrocytes contribute to dopaminergic neurodegeneration in PD

Research carried out by Professor Antonella Consiglio, Barcelona, Spain, and her colleagues supports the role of astrocytes in PD pathophysiology.

α-synuclein accumulates in control cells co-cultured with PD astrocytes

She described the studies of iPSC-derived astrocytes and neurons from familial mutant LRRK2 patients with PD and healthy individuals that demonstrated:

• neurodegeneration and abnormal astrocyte-derived α-synuclein accumulation in control ventral midbrain dopaminergic neurons (vmDAns) co-cultured with PD astrocytes
• disease-related phenotypes in PD vmDAns were partially prevented by control astrocytes
• dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes
• clearance of α-synuclein accumulation by chemical enhancement of CMA protected PD astrocytes and vmDAns⁸