Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Frontotemporal lobar degeneration (FTLD) is a primary cause of dementia and frequently co-occurs with amyotrophic lateral sclerosis (ALS).
• The precise cell type-specific molecular mechanisms driving FTLD in ALS remain largely unknown despite shared genetic and pathological links.

Purpose of the Study:

• To investigate cell type-specific molecular mechanisms in the frontal cortex of ALS patients with and without FTLD.
• To identify distinct and overlapping molecular signatures between ALS with FTLD (C9-ALS) and sporadic ALS (sALS).

Main Methods:

• Single-nucleus RNA sequencing (snRNA-seq) was employed to analyze frontal cortex tissue from ALS patients.
• Bioinformatic analyses, including APA-Net, were used to identify cell type-specific transcriptional dysregulation and RNA-binding protein (RBP) interactions.

Main Results:

• Excitatory neurons showed synaptic dysfunction in both C9-ALS and sALS, while inhibitory neurons were more impacted in sALS.
• Microglia displayed a disease-associated state, with C9-ALS showing heightened JAK-STAT signaling, indicating inflammation.
• Widespread alternative polyadenylation (APA) dysregulation was observed, with key RBPs like TDP-43 identified as regulators.

Conclusions:

• This study presents a comprehensive transcriptomic atlas of the frontal cortex in ALS with and without FTLD.
• Findings highlight cell type-specific APA and RBP dysregulation, offering novel insights into FTLD pathogenesis.
• The results provide a valuable resource for future therapeutic strategies targeting FTLD and ALS.