Pallidonigral TDP-43 pathology in Perry syndrome.

Area of Science:

• Neuroscience
• Neuropathology
• Genetics

Background:

• Perry syndrome is an early-onset, rapidly progressive autosomal dominant disorder characterized by parkinsonism, hypoventilation, depression, and weight loss.
• Previous autopsy studies revealed significant neuronal loss in the substantia nigra without Lewy bodies.
• Transactive response DNA-binding protein of 43 kDa (TDP-43) is a key component of inclusions in other neurodegenerative diseases like frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Purpose of the Study:

• To investigate the clinical, genetic, and neuropathologic features of Perry syndrome.
• To determine the role of TDP-43 in the pathogenesis of Perry syndrome.
• To screen for mutations in the progranulin (GRN) and TARDBP genes.

Main Methods:

• Collected clinical data and autopsy brain tissue from eight patients across four unrelated families with Perry syndrome.
• Utilized immunohistochemistry and biochemistry to analyze TDP-43 in brain tissue.
• Screened patients for mutations in the GRN and TARDBP genes.

Main Results:

• Identified TDP-43-positive neuronal inclusions, dystrophic neurites, and axonal spheroids in a predominantly pallidonigral distribution in all patients.
• Observed alterations in TDP-43 solubility and electrophoretic mobility in affected brain tissue.
• Found no mutations in the GRN or TARDBP genes, and TDP-43 pathology predominantly affected the extrapyramidal system, sparing the cortex, hippocampus, and motor neurons.

Conclusions:

• Perry syndrome exhibits a distinct TDP-43 neuropathology.
• The TDP-43 pathology in Perry syndrome is selectively localized to the extrapyramidal system.
• The neocortex and motor neurons are spared in Perry syndrome, differentiating it from other TDP-43 proteinopathies.