Review: Novel treatment strategies targeting alpha‐synuclein in multiple system atrophy as a model of synucleinopathy

Abstract

Neurodegenerative disorders with alpha-synuclein (α-syn) accumulation (synucleinopathies) include Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies and multiple system atrophy (MSA). Due to the involvement of toxic α-syn aggregates in the molecular origin of these disorders, developing effective therapies targeting α-syn is a priority as a disease-modifying alternative to current symptomatic treatments. Importantly, the clinical and pathological attributes of MSA make this disorder an excellent candidate as a synucleinopathy model for accelerated drug development. Recent therapeutic strategies targeting α-syn in in vivo and in vitro models of MSA, as well as in clinical trials, have been focused on the pathological mechanisms of α-syn synthesis, aggregation, clearance, and/or cell-to-cell propagation of its neurotoxic conformers. Here we summarize the most relevant approaches in this direction, with emphasis on their potential as general synucleinopathy modifiers, and enumerate research areas for potential improvement in MSA drug discovery.

Antibodies against alpha‐synuclein: tools and therapies

“…In addition to the continued use of antibodies for research and diagnosis, they are also currently being evaluated as potential therapeutic agents because of their high specificity, high binding affinity, long half lives, and low toxicity. There is no disease-modifying therapy for any synucleinopathy but previous approaches have focused on reducing a-syn expression using antisense oligonucleotides (Murphy et al 2000), miRNA (Junn et al 2009) or siRNA (Spencer et al 2019), decreasing a-syn aggregation with small molecules (Paleologou et al 2005;Ardah et al 2014Ardah et al , 2015Wrasidlo et al 2016), increasing the clearance of a-syn via autophagy (Sarkar et al 2016) and preventing the seeding and prion like spreading of a-syn (Valera et al 2016). Currently, immunotherapeutic approaches are being explored as a potential disease-modifying treatment for synucleinopathies.…”

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…SYN plays multiple pivotal roles in these diseases, nowadays its small, soluble oligomeric forms with beta-sheet conformation are considered the most toxic species [30,32,33]. To target SYN toxicity, the current strategies focus on its increased expression level (by gene silencing), aggregation (by anti-aggregation compounds), defective clearance (by autophagy inducers), and/or cell-to-cell propagation of its neurotoxic conformers (by immunotherapy, degrading enzymes) [30,34].…”

Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy

“…Its mechanisms of action are multiple, primarily involving T cell co-stimulation [14, 18, 59], increased NK cell proliferation and function [18, 59], and inhibition of the production of TNFα [13, 31, 59] and other proinflammatory cytokines [4]. We selected lenalidomide for this study because preliminary reports showed that this compound is also effective at reducing neuroinflammation in the tg mouse model used in this study ([49], and unpublished data). Moreover, these results suggest that the repurposing of FDA-approved compounds may speed up the search for an effective therapy for MSA.…”