GBA1 mutations reduce GCase activity, therefore promoting the aggregation of alpha-synuclein, a common neuropathological finding underlying Parkinson's disease (PD) and dementia with Lewy bodies.
Adult-onset neurodegenerative disorders, like Parkinson's disease (PD) and dementia with Lewy bodies (DLB), that share the accumulation of aggregated α-synuclein (αSyn<sub>agg</sub>) as their hallmark molecular pathology are collectively known as α-synucleinopathies.
Biochemical and genetic evidence point towards alpha-synuclein aggregation as having a pivotal role in the onset and progression of several neurodegenerative disorders, including Parkinson's disease, multiple system atrophy and Lewy body dementia.
Moreover, alphaSYN fibrils are the major component of Lewy bodies, the neuropathological hallmarks of Parkinson's disease and dementia with Lewy bodies as well as of glial cytoplasmic inclusions in multiple system atrophy.
To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies (DLB), a disorder closely related to Parkinson disease (PD).
Alpha-synuclein (α-syn) aggregation represents the pathological hallmark of α-synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).
The conversion of α-synuclein into oligomers and fibrils is the hallmark of a range of neurodegenerative disorders including Parkinson's disease and dementia with Lewy bodies.
Although its physiological function remains enigmatic, alpha-synuclein is implicated in movement disorders such as Parkinson's disease, multiple system atrophy, and in neurodegenerative diseases such as Dementia with Lewy bodies.
Interestingly, both PD and incidental Lewy body disease tissues showed 100% concordance for elevated levels of pathological α-synuclein seeding activity compared to control tissues.
In principle, two research approaches can be considered for the laboratory diagnosis of dementias: (i) the direct detection of disease specific protein like Abeta-peptide-oligomers in AD or alpha-synuclein-aggregates in DLB and (ii) the detection of surrogate markers that show an altered pattern of expression in early stages of the disease or are used in the differential diagnosis of other dementias and thus enable an exclusion diagnosis.
These findings suggest that variants in all 3 members of the synuclein gene family, particularly SNCA and SNCG, affect the risk of developing DLBD and warrant further investigation in larger, pathologically defined data sets as well as clinically diagnosed Parkinson disease/dementia with Lewy bodies case-control series.
The clinical features of postoperative delirium are similar to the core features of alpha synuclein-related cognitive disorders, such as Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB).
Complementing the genetic evidence linking α-synuclein to PD and DLBD is the pathological finding that α-synuclein is a major constituent of Lewy bodies and Lewy neurites in the brains of patients with the common sporadic form of PD.
The presynaptic protein alpha-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. alpha-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the alpha-synuclein gene are genetically linked to rare familial forms of Parkinson's disease.
Lewy bodies and Lewy neurites composed primarily of α-synuclein characterize synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB).
A failure of protein degradation may underpin Lewy body disease (LBD) where α-synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites.
Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication.
Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes.