Accumulation of beta-synuclein in cortical neurons is associated with autophagy attenuation in the brains of dementia with Lewy body patients.

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia, where an accumulation of aggregated fibrillar alpha-synuclein in neurons of limbic and forebrain regions of the brain leads to visual hallucination, cognitive impairment of a fluctuating nature and extrapyramidal motor disturbances. Beta-synuclein counteracts aggregation of alpha-synuclein in vitro and in animal models, however it is not clear whether this effect occurs in human Lewy body dementia (LBD) diseases. Here we examine expression of alpha-, beta-synuclein and autophagy markers in the frontal cortex (BA9) and occipital cortex (BA18-19) of patients with neuropathologically confirmed DLB/LBD and age-matched controls. We provide evidence for neuronal upregulation of beta-synuclein within the frontal cortex and its decrease in occipital cortex of DLB patients. While beta-synuclein-containing neurons were consistently devoid of oligomeric alpha-synuclein in the frontal cortex, we did not observe an overall correlation between total beta-synuclein and 5G4 levels (marker of oligomeric alpha-synuclein). The autophagy markers LC3-II and p62 were increased in the areas of beta-synuclein upregulation in DLB brains, and we show attenuation of autophagy flux when beta-synuclein is overexpressed in vitro. Altogether, this data suggests that beta-synuclein changes in DLB may exacerbate neuronal dysfunction caused by accumulation of alpha-synuclein by influencing protein degradation pathways; this should be taken into consideration when designing therapeutic strategies aimed to decrease alpha-synuclein burden in Lewy body diseases.

Evans T ，Kok WL ，Cowan K ，Hefford M ，Anichtchik O ... -  《-》

Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy.

Crews L ，Spencer B ，Desplats P ，Patrick C ，Paulino A ，Rockenstein E ，Hansen L ，Adame A ，Galasko D ，Masliah E ... -  《PLoS One》

Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies.

Higashi S ，Moore DJ ，Minegishi M ，Kasanuki K ，Fujishiro H ，Kabuta T ，Togo T ，Katsuse O ，Uchikado H ，Furukawa Y ，Hino H ，Kosaka K ，Sato K ，Arai H ，Wada K ，Iseki E ... -  《-》

The decrease of β-synuclein in cortical brain areas defines a molecular subgroup of dementia with Lewy bodies.

Beyer K ，Domingo-Sàbat M ，Santos C ，Tolosa E ，Ferrer I ，Ariza A ... -  《-》

Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies.

Kramer ML ，Schulz-Schaeffer WJ 《-》