Photo-oxygenation of histidine residue inhibits α-synuclein aggregation.

Aggregation of α-synuclein (α-syn) into amyloid is the pathological hallmark of several neurodegenerative disorders, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. It is widely accepted that α-syn aggregation is associated with neurodegeneration, although the mechanisms are not yet fully understood. Therefore, the inhibition of α-syn aggregation is a potential therapeutic approach against these diseases. This study used the photocatalyst for α-syn photo-oxygenation, which selectively adds oxygen atoms to fibrils. Our findings demonstrate that photo-oxygenation using this photocatalyst successfully inhibits α-syn aggregation, particularly by reducing its seeding ability. Notably, we also discovered that photo-oxygenation of the histidine at the 50th residue in α-syn aggregates is responsible for the inhibitory effect. These findings indicate that photo-oxygenation of the histidine residue in α-syn is a potential therapeutic strategy for synucleinopathies.

[Identification of novel regulators involved in AD pathogenesis using the CRISPR-Cas9 system].

The production of amyloid ß peptide (Aß) is an important process relating to the pathogenesis of Alzheimer disease (AD). It is widely known that the sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases lead to the production of Aß. However, the precise regulatory mechanism for Aß production remains unclear. We have established a CRISPR-Cas9 based screening system to identify the novel regulators of Aß production. Calcium and integrin-binding protein 1 (CIB1) was identified as a novel potential negative regulator of Aß production. The knockdown and knockout of Cib1 significantly increased Aß levels. In addition, immunoprecipitation showed that CIB1 interacts with the γ-secretase complex but did not alter its enzymatic activity. Moreover, Cib1 disruption specifically reduced the cell-surface localization of the γ-secretase complex. Finally, the single-cell RNA-seq analysis in the human brain demonstrated that early-stage AD patients have lower neuronal CIB1 mRNA levels compared to healthy controls. Taken together, we have shown that CIB1 controls the subcellular localization of γ-secretase, resulting in the regulation of Aß production, suggesting the involvement of CIB1 in the development of AD pathogenesis.

Attenuation of α-synuclein aggregation by catalytic photo-oxygenation.

We developed catalyst 11 to promote selective photo-oxygenation of α-synuclein amyloid and attenuate its aggregation. Catalyst 11 effectively oxygenated both small and large aggregates. The oxygenated α-synuclein exhibited lower seeding activity than intact α-synuclein. This study corroborates the feasibility of catalytic photo-oxygenation as an anti-synucleinopathy strategy.

Photo-Oxygenation as a New Therapeutic Strategy for Neurodegenerative Proteinopathies by Enhancing the Clearance of Amyloid Proteins.

Alzheimer disease (AD) is associated with the aggregation of two amyloid proteins: tau and amyloid-ß (Aß). The results of immunotherapies have shown that enhancing the clearance and suppressing the aggregation of these two proteins are effective therapeutic strategies for AD. We have developed photocatalysts that attach oxygen atoms to Aß and tau aggregates via light irradiation. Photo-oxygenation of these amyloid aggregates reduced their neurotoxicity by suppressing their aggregation both in vitro and in vivo. Furthermore, photo-oxygenation enhanced the clearance of Aß in the brain and microglial cells. Here, we describe the effects of photo-oxygenation on tau and Aß aggregation, and the potential of photo-oxygenation as a therapeutic strategy for AD, acting via microglial clearance.