Regular Paper

Acta Neuropathologica

, Volume 110, Issue 4, pp 360-368

First online:

Neuronal intranuclear inclusions are ultrastructurally and immunologically distinct from cytoplasmic inclusions of neuronal intermediate filament inclusion disease

  • Sabrina MosahebAffiliated withElectron Microscope Division, Sussex Centre for Advanced Microscopy, School of Life Sciences, University of Sussex
  • , Julian R. ThorpeAffiliated withElectron Microscope Division, Sussex Centre for Advanced Microscopy, School of Life Sciences, University of Sussex
  • , Lida Hashemzadeh-BonehiAffiliated withBiochemistry Group, School of Life Sciences, University of Sussex
  • , Eileen H. BigioAffiliated withDepartment of Neuropathology, Northwestern University Medical School
  • , Marla GearingAffiliated withDepartment of Pathology and Laboratory Medicine and Center for Neurodegenerative Disease, Emory University School of Medicine
  • , Nigel J. CairnsAffiliated withDepartment of Pathology and Immunology, Washington University School of Medicine Email author 

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Abstract

Abnormal neuronal cytoplasmic inclusions (NCIs) containing aggregates of α-internexin and the neurofilament (NF) subunits, NF-H, NF-M, and NF-L, are the signature lesions of neuronal intermediate filament (IF) inclusion disease (NIFID). The disease has a clinically heterogeneous phenotype, including frontotemporal dementia, pyramidal and extrapyramidal signs presenting at a young age. NCIs are variably ubiquitinated and about half of cases also have neuronal intranuclear inclusions (NIIs), which are also ubiquitinated. NIIs have been described in polyglutamine-repeat expansion diseases, where they are strongly ubiquitin immunoreactive. The fine structure of NIIs of NIFID has not previously been described. Therefore, to determine the ultrastructure of NIIs, immunoelectron microscopy was undertaken on NIFID cases and normal aged control brains. Our results indicate that the NIIs of NIFID are strongly ubiquitin immunoreactive. However, unlike NCIs which contain ubiquitin, α-internexin and NF epitopes, NIIs contain neither epitopes of α-internexin nor NF subunits. Neither NIIs nor NCIs were recognised by antibodies to expanded polyglutamine repeats. The NII of NIFID lacks a limiting membrane and contains straight filaments of 20 nm mean width (range 11–35 nm), while NCIs contain filaments with a mean width of 10 nm (range 5–18 nm; t-test, P<0.001). Biochemistry revealed no differences in neuronal IF protein mobilities between NIFID and normal brain tissue. Therefore, NIIs of NIFID contain filaments morphologically and immunologically distinct from those of NCIs, and both types of inclusion lack expanded polyglutamine tracts of the triplet-repeat expansion diseases. These observations indicate that abnormal protein aggregation follows separate pathways in different neuronal compartments of NIFID.

Keywords

Neuronal intermediate filament inclusion disease Ubiquitin α-Internexin Neurofilament Frontotemporal dementia