Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology.
Neurodegeneration with brain iron accumulation, type 1 (NBIA 1), or Hallervorden-Spatz syndrome, is a rare neurodegenerative disorder characterized clinically by Parkinsonism, cognitive impairment, pseudobulbar features, as well as cerebellar ataxia, and neuropathologically by neuronal loss, gliosis, and iron deposition in the globus pallidus, red nucleus, and substantia nigra. The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur. Here we show that there is an accumulation of alpha-synuclein (alphaS) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients. Further, beta-synuclein (betaS) and gamma-synuclein (gammaS) immunoreactivity was detected in spheroids but not in LB-like or glial inclusions. Western blot analysis demonstrated high-molecular weight alphaS aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain. Significantly, the levels of alphaS were markedly reduced in the Triton X-100-soluble fractions compared to control brain, and unlike other synucleinopathies, insoluble alphaS did not accumulate in the formic acid-soluble fraction. These findings expand the concept of neurodegenerative synucleinopathies by implicating alphaS, betaS, and gammaS in the pathogenesis of NBIA 1.
Department of Neurology, Medical College of Pennsylvania Hahnemann University. the Center for Neurodegenerative Disease Research, and the Department of Neurology, the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J E
JE
Galvin
B
B
Giasson
H I
HI
Hurtig
V M
VM
Lee
J Q
JQ
Trojanowski
D000293:Adolescent; D000368:Aged; D016229:Amyloid beta-Peptides / Q000032:analysis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D017809:Fatal Outcome; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007501:Iron / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000032:analysis*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein; D016875:tau Proteins / Q000032:analysis
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497607:SNCB protein, human; D051843:Synucleins; D051844:alpha-Synuclein; D051846:beta-Synuclein; D051845:gamma-Synuclein; D016875:tau Proteins; D007501:Iron