Induced pluripotent stem cells in multiple system atrophy: recent developments and scientific challenges

Abstract

Multiple system atrophy (MSA) is a rare and fatal neurodegenerative disease, with no known genetic cause to date. Oligodendroglial α-synuclein accumulation, neuroinflammation, and early myelin dysfunction are hallmark features of the disease and have been modeled in part in various preclinical models of MSA, yet the pathophysiology of MSA remains elusive. Here, we review the role and scientific challenges of induced pluripotent stem cells in the detection of novel biomarkers and druggable targets in MSA.

Neuropathology of multiple system atrophy: Kurt Jellinger`s legacy

“…To date three main approaches have been used to develop animal models of MSA (Table 1 ) based, respectively, on the use of neurotoxins selectively damaging the nigrostriatal or olivopontocerebellar structures, recombinant genetic techniques and viral vectors aiming at inducing α-synuclein overexpression in oligodendrocytes (Jellinger 2019b ; Lee et al 2019 ). A further in vitro model of MSA based on the use of induced pluripotent stem cells has been recently proposed (Abati et al 2018 ; Monzio Compagnoni et al 2018 ; Nakamoto et al 2018 ; Ndayisaba et al 2019 ; Herrera-Vaquero et al 2021 ). Moreover, models based on the inoculation of MSA patients’ brain-derived homogenates in α-synuclein overexpressing mice have been shown to reproduce the α-synuclein prion-like spreading pattern.…”

Stem Cell Therapies in Movement Disorders: Lessons from Clinical Trials

“…These studies have not been followed by others on wider number of patients and other MSA subtypes; additionally, some of these studies have been published more than a decade ago without further confirmation studies [26], thus suggesting limited applications of stem cells for MSA patients. Furthermore, as multiple systems and cell types are affected in MSA, different cell types may be needed for a stem-cell based therapeutic approach in this condition [31].…”