Quantitative patterns of motor cortex proteinopathy across ALS genotypes

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is characterized by motor cortex degeneration and protein aggregate accumulation.
• The quantitative burden and pattern of motor cortex proteinopathies across different ALS genetic subtypes remain poorly understood.

Purpose of the Study:

• To investigate the relationship between ALS genotype, total proteinopathy load, and cellular vulnerability to aggregate formation in the primary motor cortex.
• To explore genotype-specific patterns of protein aggregation and glial activation in ALS.

Main Methods:

• Quantitative digital image analysis of post-mortem brain tissue from 82 ALS cases.
• Multi-level generalized linear modeling to assess genotype-specific proteinopathy burden.

Main Results:

• Sporadic ALS-TDP exhibited higher phosphorylated (p)TDP-43 burden and microglial activation in the motor cortex compared to C9-ALS.
• Oligodendroglial pTDP-43 pathology was prevalent across various ALS subtypes, including sporadic ALS, C9-ALS, and those with OPTN, HNRNPA1, or TARDBP mutations.
• ALS-FUS and ALS-SOD1 showed less cortical proteinopathy relative to spinal cord pathology compared to ALS-TDP.
• Neuronal pTDP-43 aggregates were primarily found in excitatory neurons, sparing inhibitory interneurons.
• Cortical microglia, but not astrocytes, were found to contain pTDP-43.

Conclusions:

• Findings suggest divergent, genotype-specific vulnerabilities of the ALS primary motor cortex to proteinopathies.
• These insights may inform the development of genotype-specific therapies for ALS.