Calpain in the cleavage of alpha-synuclein and the pathogenesis of Parkinson's disease

Abstract

Parkinson's disease (PD) devastates 6.3 million people, ranking it as one of the most prevalent neurodegenerative motor disorders worldwide. PD patients may manifest symptoms of postural instability, bradykinesia, and resting tremors as a result of increasing α-synuclein aggregation and neuron death with disease progression. Therapy options are limited, and those available to patients may worsen their condition. Thus, investigations to understand disease progression may help develop therapeutic strategies for improvement of quality of life for patients suffering from PD. This review provides an overview of α-synuclein, a presynaptic neuronal protein whose function in the healthy brain and PD pathology remains a mystery. This review also focuses on calcium-induced activation of calpain, a neutral protease, and the subsequent cascade of cellular processing of α-synuclein and emerging defense responses observed in experimental models of PD: microglial activation, dysregulation of T cells, and inflammatory responses in the brain. In addition, this review discusses the events of cross presentation of synuclein peptides by professional antigen presenting cells and microglia, induction of inflammatory responses in the periphery and brain, and emerging calpain-targeted therapeutic strategies to attenuate neuronal death in PD.

Keywords: Alpha-synuclein; Calpain; Inflammation; Microglia; Neurodegeneration; Parkinson's disease; T cells.

Figure 1:. Calpain activation, α-synuclein degradation, and microglial response in the brain.

When there is increased calcium signaling in the brain, calpain is upregulated. Upregulation of calpain induces activation of microglia, which may promote multiple pathways of immune activation. Upon calpain activation, activated microglia can degrade α-synuclein and present immunogenic synuclein peptides to T cells, activating immune response, and inducing inflammation. Inhibition of calpain activation may downregulate microglia-mediated inflammatory responses in the brain, thereby attenuating inflammation. On the other hand, calpain activation can cause generation of toxic synuclein peptides and inflammatory T cells, which may induce neuronal cell death.

Figure 2:. Cross presentation of α-synuclein peptides to microglia in the brain.

When the body elicits an immune response, dendritic cells, B-cells, and macrophages can be activated as a part of this immune response. Upon activation, these APCs can process and present synuclein to activate T cells. Calpain processing of synuclein may occur in the endolysosomal compartmets producing MHC-peptide complexes to be captured by other non-professional APCs for immune activation. Gamma-interferon-inducible lysosomal thiol reductase (GILT), and non-classical class II molecules (HLM-DO and HLA-DM) in APCs can modulate immune responses in the host. The processed synuclein peptides can also be transported across the blood brain barrier and presented to microglia for T cell activation and induction of neuroinflammation.