Lewy body dementia is the second most common neurodegenerative
dementia and is pathologically characterized by α-
synuclein positive cytoplasmic inclusions, with varying amounts of
amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional
ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived
proteins, may be a mediating factor of
disease progression and of the development of α-
synuclein aggregates. In the present study,
protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (
chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus' cortex were selected as regions of interest from
Parkinson's disease dementia (PDD, n = 31),
dementia with Lewy bodies (DLB, n = 44),
Alzheimer's disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and
cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in
Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of
cognitive impairment in DLB and PDD.