Neuropathological spectrum of synucleinopathies

Abstract

Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.