[FTLD/ALS as TDP-43 proteinopathies].

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Context:

• Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) frequently co-occur, presenting as FTLD/MND.
• The precise relationship between FTLD/MND, ALS, and FTLD remains unclear.
• TAR DNA binding protein 43 KDa (TDP-43) is a major component of inclusion bodies in these neurodegenerative diseases.

Purpose:

• To investigate whether FTLD/MND is a distinct entity from ALS and FTLD.
• To explore the role of TDP-43 in the pathogenesis of ALS, FTLD, and FTLD/MND.
• To analyze the distribution patterns of TDP-43 inclusion bodies in ALS patients.

Summary:

• TDP-43 mutations are common in ALS, suggesting a primary role in its pathogenesis.
• Few TDP-43 mutations are found in FTLD, indicating it may not be primary in FTLD.
• ALS exhibits subtypes based on TDP-43 inclusion body distribution; familial FTLD/MND genes are not linked to TDP-43.

Impact:

• Suggests FTLD/MND is a distinct disease entity separate from ALS and FTLD.
• Highlights the differential involvement of TDP-43 in the pathogenesis of these related neurodegenerative disorders.
• Provides a basis for refining diagnostic criteria and understanding the molecular mechanisms underlying FTLD/MND.