Integrated Stress Response Signatures Drive Monocyte Dysfunction in GBA1- and LRRK2-Linked Parkinson's Disease

Area of Science:

• Neuroimmunology
• Cellular Biology
• Genetics

Background:

• Monocytes play a role in Parkinson's disease (PD) pathogenesis, with known mitochondrial and lysosomal issues in idiopathic PD.
• The effect of PD-associated mutations (GBA1, LRRK2) on monocyte function is not well understood.

Purpose of the Study:

• To investigate transcriptomic and functional changes in peripheral monocytes from patients with GBA1-PD, LRRK2-PD, and idiopathic PD.
• To define the molecular and functional characteristics of monocytes in different PD subtypes.

Main Methods:

• Transcriptomic analysis of monocytes from PD patients and controls.
• Network and pathway analyses to identify dysregulated biological processes.
• Assessment of protein levels (heat-shock proteins, ISR effectors) and live-cell assays for lysosomal function, mitochondrial dynamics, and phagocytosis.

Main Results:

• Shared and mutation-specific transcriptomic signatures were identified, including immune dysregulation and defects in lysosomal, proteasomal, and mitochondrial pathways.
• Downregulation of protein translation and enrichment of integrated stress response (ISR) signatures were observed.
• Impaired proteostasis, lysosomal function, mitochondrial dynamics, and phagocytosis were evident across all PD groups, particularly in GBA1- and LRRK2-associated PD.

Conclusions:

• Parkinson's disease is associated with a myeloid state of 'immunodegeneration'.
• This state is characterized by impaired cellular clearance, proteostasis failure, and mitochondrial dysfunction.
• These defects are present in monocytes across genetic and idiopathic forms of Parkinson's disease.