Anle138b modulates α‐synuclein oligomerization and prevents motor decline and neurodegeneration in a mouse model of multiple system atrophy

Abstract

Background MSA is a fatal neurodegenerative disease characterized by autonomic failure and severe motor impairment. Its main pathological hallmark is the accumulation of α‐synuclein in oligodendrocytes, leading to glial and neuronal dysfunction and neurodegeneration. These features are recapitulated in the PLP‐hαSyn mouse model expressing human α‐synuclein in oligodendrocytes. At present, there is no effective disease‐modifying therapy. Previous experiments have shown that the aggregation inhibitor, anle138b, reduces neurodegeneration and behavioral deficits in mouse models of other proteinopathies. Objectives To test the therapeutic potential of anle138b in a mouse model of MSA. Methods Two‐month‐old PLP‐hαSyn mice were fed over a period of 4 months with pellets containing anle138b at two different doses (0.6 and 2 g/kg) and compared to healthy controls and PLP‐hαSyn mice fed with placebo pellets. At the end of the treatment, behavioral and histological analyses were performed. Results We observed a reversal of motor function to healthy control levels when PLP‐hαSyn mice were treated with both doses of anle138b. Histological and molecular analyses showed a significant reduction in α‐synuclein oligomers and glial cytoplasmic inclusions in animals fed with anle138b compared to nontreated mice. These animals also present preservation of dopaminergic neurons and reduction in microglial activation in SN correlating with the α‐synuclein reduction observed. Conclusions Anle138b reduces α‐synuclein accumulation in PLP‐hαSyn mice, leading to neuroprotection, reduction of microglial activation, and preservation of motor function supporting the use of anle138b in a future clinical trial for MSA. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model

“…We show that progressive DA dysfunction is associated with increased formation of synaptic striatal αSyn aggregates. Moreover, we show that the oligomer modulator, anle138b, previously shown to be effective in other models of protein aggregation including αSyn (Heras-Garvin et al, 2018;Martinez Hernandez et al, 2018;Wagner et al, 2015;Wagner et al, 2013) , restores striatal DA release and prevents DA cell loss even when administration is started after the onset of DA dysfunction. For the first time and using dSTORM and immunoblotting, we show that in vivo, in mouse brain, anle138b rescue of the DA deficit is associated with reduction of the density of large αSyn aggregates and an increase in dispersed monomeric and small assemblies of 1-120hαSyn.…”

“…We then used MI2 mice to test whether DA pathology might be rescued by targeting neuronal αSyn aggregation with anle138b, which has previously been shown to have beneficial effects by interacting specifically with structural epitopes of various protein aggregates and to rescue protein aggregation and related pathological features in models with αSyn, prion and tau aggregation (Martinez Hernandez et al, 2018;Wagner et al, 2015;Wagner et al, 2013). Unlike the MI2 mice, the αSyn transgenic models used in previous anle138b studies did not present with consistent neuronal nigrostriatal αSyn aggregation or αSyn-related progressive dopaminergic impairment with motor impairment related in some cases more to spinal cord pathology (Wagner et al, 2013) or αSyn pathology in oligodendrocytes (Heras-Garvin et al, 2018). Thus, our study is the first to investigate the effects of anle138b in a model with nigrostriatal neuronal DA alterations and neuronal αSyn aggregation as observed in PD.…”

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

“…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 . Of note, Anle138b is one of the few compounds successfully tested in vivo, since most of the molecules mentioned above have been tested on different cell lines or even in cell‐free models of α‐syn fibrillation (all the compounds mentioned are summarized in Table ).…”

“…47 Finally, Anle138b, a small compound with high bioavailability and low toxicity, 48 decreases α-syn oligomerization and aggregation and reduces motor impairment and degeneration in MSA and PD mouse models. 29,49 Of note, Anle138b is one of the few compounds successfully tested in vivo, since most of the molecules mentioned above have been tested on different cell lines or even in cell-free models of α-syn fibrillation (all the compounds mentioned are summarized in Table 1). Speaking of ways to reduce the burden of α-syn aggregates, it is worth mentioning intracellular antibodies (usually referred as intrabodies) are recombinant antibody fragments that bind to target proteins expressed inside of the same living cell producing the antibodies.…”

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

“…Anle 138b is a promising neuroprotectant also in other NDDs associated to toxic protein deposition. Indeed, the compound showed capability to inhibit oligomer accumulation, neuronal degeneration, and disease progression in vivo in three PD models [82] and has recently been tested with success in an animal model of Multiple System Atrophy [83].…”