Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Amyotrophic lateral sclerosis (ALS) exhibits predictable spatiotemporal spread of symptoms and pathology.
• Protein aggregates, including TDP-43, SOD1, and C9orf72 dipeptide repeat proteins (DPRs), are hallmarks of ALS.
• TDP-43 aggregates are found in most ALS cases, while SOD1 and C9orf72 aggregates are specific to certain subtypes.

Purpose of the Study:

• To examine the cell-to-cell propagation mechanisms of ALS-associated protein aggregates.
• To correlate the spread of pathological proteins with disease progression in ALS patients.
• To investigate the distinct transmission properties of TDP-43, SOD1, and C9orf72 DPRs.

Main Methods:

• Review of literature on protein aggregation and intercellular transport in ALS.
• Analysis of spatiotemporal patterns of disease spread and protein pathology.
• Comparison of prion-like seeding (TDP-43, SOD1) versus general disease state induction (C9orf72 DPRs).

Main Results:

• Cell-to-cell propagation of pathological proteins correlates with contiguous disease spread in ALS.
• TDP-43 and SOD1 aggregates exhibit prion-like seeding capabilities.
• C9orf72 DPRs appear to induce and transmit a broader 'disease state'.
• Intercellular transport occurs via axonal transport, extracellular vesicles, and macropinocytosis, involving both neurons and glia.

Conclusions:

• Understanding the mechanisms of protein aggregate propagation is vital for ALS research.
• Intercellular transmission of TDP-43, SOD1, and C9orf72 proteins contributes to ALS pathogenesis.
• Targeting these propagation pathways may offer therapeutic strategies for ALS.