Absence of heparan sulfate proteoglycans in Lewy bodies and Lewy neurites in Parkinson's disease brains.

alpha-Synuclein is the major constituent of Lewy bodies and Lewy neurites in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Relatively little is known about the exact mechanism of alpha-synuclein deposition and fibrillization in these alpha-synucleinopathies. In order to better understand the pathogenesis of alpha-synucleinopathies it is important to identify molecules that regulate the fibrillization of alpha-synuclein. Since it has been demonstrated that heparan sulfate proteoglycans (HSPGs) and glycosaminoglycans (GAGs) promote the conversion of non-fibrillar amyloid beta-protein (Abeta) into neurotoxic fibrillar Abeta in Alzheimer's disease, they might also be involved in alpha-synuclein aggregation. It was the aim of our study to examine the distribution pattern of these macromolecules in PD brains and the possible association with Lewy bodies and Lewy neurites. Although HSPGs clearly colocalized with senile plaques, we were unable to identify HSPGs or GAGs in Lewy bodies and Lewy neurites and therefore concluded that it is likely that alpha-synuclein fibrillization and stabilization occurs independently of the presence of HSPGs or GAGs.

Elevated concentration of cerebrospinal fluid tissue transglutaminase in Parkinson's disease indicating apoptosis.

Tissue transglutaminase (tTG) is activated during the apoptotic cell death cascade and plays a key role in the formation of apoptotic bodies. We found significant elevation of tTG concentration in the cerebrospinal fluid (CSF) of 54 patients with Parkinson's disease (PD) compared with that measured in 34 control subjects, thus showing increased neural cell apoptosis in patients with PD.

Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain.

Molecular misreading of the ubiquitin-B (UBB) gene results in a dinucleotide deletion in UBB mRNA. The resulting mutant protein, UBB+1, accumulates in the neuropathological hallmarks of Alzheimer disease. In vitro, UBB+1 inhibits proteasomal proteolysis, although it is also an ubiquitin fusion degradation substrate for the proteasome. Using the ligase chain reaction to detect dinucleotide deletions, we report here that UBB+1 transcripts are present in each neurodegenerative disease studied (tauo- and synucleinopathies) and even in control brain samples. In contrast to UBB+1 transcripts, UBB+1 protein accumulation in the ubiquitin-containing neuropathological hallmarks is restricted to the tauopathies such as Pick disease, frontotemporal dementia, progressive supranuclear palsy, and argyrophilic grain disease. Remarkably, UBB+1 protein is not detected in the major forms of synucleinopathies (Lewy body disease and multiple system atrophy). The neurologically intact brain can cope with UBB+1 as lentivirally delivered UBB+1 protein is rapidly degraded in rat hippocampus, whereas the K29,48R mutant of UBB+1, which is not ubiquitinated, is abundantly expressed. The finding that UBB+1 protein only accumulates in tauopathies thus implies that the ubiquitin-proteasome system is impaired specifically in this group of neurodegenerative diseases and not in synucleinopathies and that the presence of UBB+1 protein reports proteasomal dysfunction in the brain.