Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Repetitive head impacts are linked to TDP-43 pathology, particularly in the hippocampus and frontal cortex, a hallmark of chronic traumatic encephalopathy (CTE).
• TDP-43 inclusions in CTE correlate with severe cognitive impairment, but the underlying mechanisms remain unclear.
• TDP-43 pathology in other neurodegenerative diseases like ALS and FTLD-TDP is associated with gene mis-splicing and cryptic exon expression.

Purpose of the Study:

• To investigate whether TDP-43 pathology in CTE contributes to gene mis-splicing, selective protein loss, and subsequent neurodegeneration.
• To identify specific genes affected by mis-splicing and protein reduction in CTE with TDP-43 inclusions.
• To explore the association between these molecular changes and cognitive impairment in CTE.

Main Methods:

• Examined 212 brain donors with repetitive head impact history for CTE and TDP-43 inclusions.
• Performed bulk RNA sequencing and proteomics on the dorsolateral prefrontal cortex.
• Analyzed variable splicing events using LeafCutter in CTE cases with (CTE-TDP) and without TDP-43 inclusions in the hippocampus or frontal cortex.

Main Results:

• 51% of CTE cases (72/142) exhibited TDP-43 inclusions (CTE-TDP).
• Altered splicing was found in 836 genes in CTE-TDP compared to CTE (FDR <0.01), with 23 overlapping with ALS/FTLD-TDP.
• Significantly reduced protein levels of EPB41L1 and RAP1GAP were observed in CTE-TDP, correlating with TDP-43 load and associated with dementia.

Conclusions:

• EPB41L1 and RAP1GAP are crucial for synaptic plasticity and signaling.
• Gene mis-splicing and reduced protein expression of EPB41L1 and RAP1GAP may contribute to neurodegeneration and cognitive deficits in CTE with TDP-43 pathology.
• These findings elucidate a potential molecular mechanism linking head trauma, TDP-43 pathology, and cognitive impairment in CTE.