Lewy bodies are intracellular fibrillar inclusions composed of α-synuclein. They constitute the pathological hallmark of Parkinson's disease, dementia with Lewy bodies, and other neurodegenerative diseases. Although the majority of Lewy bodies are stained for ubiquitin by immunohistochemistry, the substrate for this modification is poorly understood. Insoluble, urea-soluble α-synuclein was separated from soluble fractions and subjected to two-dimensional gel electrophoresis to further characterize pathogenic α-synuclein species from disease brains. By using this approach, we found that in sporadic Lewy body diseases a highly modified, disease-associated 22–24-kDa α-synuclein species is ubiquitinated. Conjugation of one, two, and, to a lesser extent, three ubiquitins was detected. This 22–24-kDa α-synuclein species represents partly phosphorylated protein. Furthermore, no generalized impairment of the proteolytic activity of the proteasome was detected in brain regions with Lewy body pathology. Because unmodified α-synuclein is degraded by the proteasome in a ubiquitin-independent manner, these data suggest that accumulation of modified 22–24-kDa α-synuclein is a disease-specific event which may overwhelm the proteolytic system, leading to aberrant ubiquitination. Accordingly, carboxyl-terminal-truncated α-synuclein, presumably the result of aberrant proteolysis, is found only in association with α-synuclein aggregates.

Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial “multiple system tauopathy with presenile dementia,” which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of β-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.

Dysfunction of the 140 aa protein α-synuclein plays a central role in Lewy body disorders, including Parkinson’s disease, as well as in multiple system atrophy. Here, we show that the expression of truncated human α-synuclein(1–120), driven by the rat tyrosine hydroxylase promoter on a mouse α-synuclein null background, leads to the formation of pathological inclusions in the substantia nigra and olfactory bulb and to a reduction in striatal dopamine levels. At the behavioral level, the transgenic mice showed a progressive reduction in spontaneous locomotion and an increased response to amphetamine. These findings suggest that the C-terminal of α-synuclein is an important regulator of aggregationin vivoand will help to understand the mechanisms underlying the pathogenesis of Lewy body disorders and multiple system atrophy.

The pre-synaptic protein α-synuclein is the main component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson’s disease and dementia with Lewy bodies. Mutations in the α-synuclein gene cause familial forms of Parkinson’s disease and dementia with Lewy bodies. We previously described a transgenic mouse line expressing truncated human α-synuclein(1-120) that develops α-synuclein aggregates, striatal dopamine deficiency and reduced locomotion, similar to Parkinson’s disease. We now show that in the striatum of these mice, as in Parkinson’s disease, synaptic accumulation of α-synuclein is accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and synaptobrevin-2, as well as by an age-dependent reduction in dopamine release. Furthermore, the release of FM1-43 dye from PC12 cells expressing either human full-length α-synuclein(1–140) or truncated α-synuclein(1-120) was reduced. These findings reveal a novel gain of toxic function of α-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson’s disease.