[Recent progress in ALS research: ALS and TDP-43].

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Context:

• Amyotrophic lateral sclerosis (ALS) traditionally focuses on motor neuron degeneration.
• Emerging evidence reveals broader neurological involvement in ALS, ALS-dementia (ALS-D), and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U).
• The discovery of ubiquitin-positive inclusions (UbIs) marked a shift in understanding these conditions.

Purpose:

• To highlight the central role of TAR DNA-binding protein 43 (TDP-43) in a spectrum of neurodegenerative diseases.
• To connect TDP-43 pathology to ALS, ALS-D, FTLD-U, and related syndromes like parkinsonism-dementia complex (PDC).
• To underscore the significance of TDP-43 mutations in familial ALS.

Summary:

• TAR DNA-binding protein 43 (TDP-43) is identified as the core protein in ubiquitin-positive inclusions found in ALS, ALS-D, and FTLD-U.
• Abnormalities, including ubiquitination and phosphorylation of TDP-43, are characteristic findings in these conditions and related syndromes.
• Mutations in the TDP-43 gene are causative in a significant subset of familial ALS cases.

Impact:

• TDP-43 is now recognized as a key protein in the pathogenesis of TDP-43 proteinopathies.
• This understanding is crucial for developing targeted molecular mechanisms and therapies for ALS and related disorders.
• Further research into TDP-43 is expected to revolutionize ALS treatment strategies.