Ade novocompound targeting α-synuclein improves deficits in models of Parkinson’s disease

Abstract

Abnormal accumulation and propagation of the neuronal protein α-synuclein has been hypothesized to underlie the pathogenesis of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Here we report a de novo-developed compound (NPT100-18A) that reduces α-synuclein toxicity through a novel mechanism that involves displacing α-synuclein from the membrane. This compound interacts with a domain in the C-terminus of α-synuclein. The E83R mutation reduces the compound interaction with the 80-90 amino acid region of α-synuclein and prevents the effects of NPT100-18A. In vitro studies showed that NPT100-18A reduced the formation of wild-type α-synuclein oligomers in membranes, reduced the neuronal accumulation of α-synuclein, and decreased markers of cell toxicity. In vivo studies were conducted in three different α-synuclein transgenic rodent models. Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type α-synuclein transgenic mice in a dose-dependent manner at two independent institutions. Neuropathological examination showed that NPT100-18A decreased the accumulation of proteinase K-resistant α-synuclein aggregates in the CNS and was accompanied by the normalization of neuronal and inflammatory markers. These results were confirmed in a mutant line of α-synuclein transgenic mice that is prone to generate oligomers. In vivo imaging studies of α-synuclein-GFP transgenic mice using two-photon microscopy showed that NPT100-18A reduced the cortical synaptic accumulation of α-synuclein within 1 h post-administration. Taken together, these studies support the notion that altering the interaction of α-synuclein with the membrane might be a feasible therapeutic approach for developing new disease-modifying treatments of Parkinson's disease and other synucleinopathies.

Antibodies against alpha‐synuclein: tools and therapies

“…, ; Wrasidlo et al . ), increasing the clearance of α‐syn via autophagy (Sarkar et al . ) and preventing the seeding and prion like spreading of α‐syn (Valera et al .…”

Progress of Pharmacological Approaches in Parkinson's Disease

“…A third preclinical molecule, NPT100-18A, reduces the formation of wild-type aSYN-oligomers in membranes, alleviates the neuronal accumulation of aSYN, and decreases markers of cell toxicity. 44 Treatment with NPT100-18A ameliorated motor deficits in mThy1 wild-type aSYN transgenic mice in a dosedependent manner. 44 It has not yet been tested in clinical trials.…”

The good and bad of therapeutic strategies that directly target α‐synuclein

“…A class of small compounds recently conceived to specifically target oligomeric forms of α‐syn have been successfully tested in multiple in vivo models of PD. NPT100‐18A was designed to target membrane‐bound α‐syn and to counteract oligomerization, while NPT200‐11 was optimized to bind specific regions of α‐syn thought to be responsible oligomerization into toxic forms and also to be orally bioavailable and brain penetrating . Finally, Anle138b, a small compound with high bioavailability and low toxicity, decreases α‐syn oligomerization and aggregation and reduces motor impairment and degeneration in MSA and PD mouse models .…”