Proteolytic processing regulates pathological accumulation in dentatorubral-pallidoluysian atrophy

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disorder caused by polyglutamine (polyQ) expansion in the atrophin-1 (ATN1) protein.
• Nuclear accumulation of ATN1 and its fragments with expanded polyQ is implicated in DRPLA pathogenesis.
• The precise mechanisms governing ATN1 proteolytic processing and subsequent accumulation remain poorly understood.

Purpose of the Study:

• To investigate the proteolytic processing of ATN1 and elucidate the mechanisms behind polyQ-expanded ATN1 accumulation.
• To identify and characterize novel ATN1 fragments involved in DRPLA pathology.

Main Methods:

• Utilized COS-7 and Neuro2a cell lines expressing ATN1 with varying polyQ lengths.
• Employed immunocytochemical and biochemical analyses to study ATN1 fragment localization and accumulation.
• Investigated the role of caspases in ATN1 fragment processing.

Main Results:

• Identified a novel C-terminal ATN1 fragment containing a polyQ tract.
• Demonstrated selective accumulation of the mutant C-terminal fragment in cells and DRPLA patient brain tissues.
• Found that the mutant C-terminal fragment localizes to the cytoplasmic membrane/organelle and insoluble fractions.
• Observed enhanced accumulation of the C-terminal fragment upon caspase inhibition.

Conclusions:

• Proteolytic processing of ATN1 significantly influences the localization of its C-terminal fragments.
• The C-terminal ATN1 fragment plays a crucial role in the pathological accumulation of ATN1 in DRPLA.
• Targeting the processing or accumulation of this C-terminal fragment may offer therapeutic strategies for DRPLA.