A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Parkinson's disease (PD) involves α-synuclein aggregation in dopaminergic neurons.
• Proteolysis of α-synuclein can facilitate aggregation and impact cell viability.
• Glutaminyl cyclase (QC) is hypothesized to modify α-synuclein fragments, potentially exacerbating PD pathology.

Purpose of the Study:

• To investigate the role of glutaminyl cyclase (QC) in the formation of pyroglutamate α-synuclein (pGlu79-α-synuclein).
• To characterize the aggregation properties and neurotoxicity of pGlu79-α-synuclein.
• To determine the presence and localization of pGlu79-α-synuclein and QC in PD and dementia with Lewy body (DLB) brains.

Main Methods:

• Enzymatic assays and mass spectrometry to analyze QC activity on Gln79-α-synuclein.
• Thioflavin T assays, electron microscopy, and size exclusion chromatography to assess α-synuclein aggregation.
• Cell viability assays to measure neurotoxicity.
• Immunohistochemistry using specific antibodies in transgenic mouse models and human brain samples from PD/DLB patients.

Main Results:

• QC catalyzes the conversion of Gln79-α-synuclein to pGlu79-α-synuclein.
• pGlu79-α-synuclein exhibits reduced fibril formation but increased formation of toxic oligomeric aggregates.
• QC and pGlu79-α-synuclein are co-expressed and co-localized in dopaminergic neurons of the substantia nigra in PD and DLB brains.
• pGlu79-α-synuclein is found within Lewy bodies and dystrophic neurites in human PD/DLB brains.

Conclusions:

• QC promotes the formation of aggregation-prone and neurotoxic pGlu79-α-synuclein in human synucleinopathies.
• pGlu79-α-synuclein may act as a critical seed for pathogenic protein aggregation in PD and DLB.
• Targeting QC could offer a novel therapeutic strategy for synucleinopathies.