Table 1.

Overview of in vitro and in vivo models of MSA

In vitro models
Model	Cell line	Mechanism	Features
U-373 MG (Stefanova et al. 2005)	Human glioblastoma astrocytoma cells	Overexpression of α-synuclein	Increased susceptibility to oxidative stress and neuroinflammation
OLN-93 (Kragh et al. 2009)	Rat oligodendrocytes	Overexpression of α-synuclein and p25α	Impaired microtubules remodeling and promoted apoptosis
CG4 (May et al. 2014)	Rodent oligodendrocytes	Overexpression of α-synuclein	Impaired cellular maturation due to the inhibition of MBP expression
iPSCs (Nakamoto et al. 2018)	Human-induced pluripotent stem cells	In vitro differentiation	Mitochondrial deficits
iPSCs (Monzio Compagnoni et al. 2018)	Human-induced pluripotent stem cells	In vitro differentiation	Mitochondrial deficits
iPSCs (Herrera-Vaquero et al. 2021)	Human-induced pluripotent stem cells	In vitro differentiation	Mitochondrial deficits, increased susceptibility to oxidative stress

In vivo models
Model	Specie(s)	Neuropathology	Clinical phenotype	Features
Neurotoxin-based
6-OHDA + QA (Wenning et al. 1996a)	Rat (intrastriatal)	Striatonigral degeneration (without GCIs)	Poorly L-Dopa responsive motor impairment (akinesia, rigidity); no autonomic features	GCIs pathology not reproduced Lesions fail to spread outside basal ganglia No autonomic impairment
MPTP + 3-NP (Ghorayeb et al. 2000; Stefanova et al. 2003)	Mouse, non-human primate (intrastriatal, systemic – e.g., i.v., i.p.)	Striatonigral degeneration (without GCIs)	Poorly L-Dopa responsive motor impairment (akinesia, rigidity); no autonomic features	GCIs pathology not reproduced Lesions fail to spread outside basal ganglia No autonomic impairment
Transgenic α-synuclein overexpression models
PLP α-syn (Kahle et al. 2002)	Mouse	Striatonigral degeneration (with GCIs), loss of neurons in central autonomic centers of CNS and spinal cord; OPCA appears when triggered by treatment with 3-NP; GCIs-related microglial activation	Autonomic dysfunction predating motor deficits (exacerbated by treatment with 3-NP). Intact olfaction; sleep structure disruption resembling RBD	Both autonomic and motor dysfunction are replicated; Only model showing GCI-related microglial activation; The mild motor phenotype represents the main limitation
CNP α-syn (Yazawa et al. 2005)	Mouse	Striatonigral, cerebellar, callosal and cortical demyelination and axonal degeneration (with α-synuclein glial inclusions); severe astrogliosis	Motor deficits (exacerbated by treatment with 3-NP)	Pathological substrate of motor deterioration seems to be different from SND and OPCA; Useful to assess protein interactions
MBP α-syn (Shults et al. 2005)	Mouse	Disrupted axonal integrity in striatum, brainstem, cerebellum without neuronal loss in SN (with α-synuclein glial inclusions); mild demyelination and astrocytosis of white matter tracts	Motor deficits. High expressor line 29 shows reduced survival, mild expressor line 1 shows preserved survival but with mild motor phenotype	Pathological substrate differs from human MSA (e.g., no SN neuronal loss); No microglial activation; Useful in recapitulating key pathogenetic mechanisms
Viral-mediated α-synuclein overexpression models
AAV Olg001 (Mandel et al. 2017)	Non-human primate	Demyelination of white matter tracts and corpus callosum, microgliosis in the striatum (with widespread α-synuclein glial inclusions)	Needs to be better assessed	Recapitulates some main neuropathological and clinical features of MSA but deserves further validation
AAV1/2 MBP promotor (Bassil et al. 2017)	Rat, non-human primate (macaque)	Dopaminergic cell loss (with widespread α-synuclein glial inclusions)	L-Dopa unresponsive progressive motor deficits	Recapitulates some main neuropathological and clinical features of MSA but deserves further validation
α-synuclein spreading models
Tg83 ± mouse inoculated with MSA-derived α-synuclein (intracerebral and peripheral inoculation) (Watts et al. 2013; Prusiner et al. 2015; Ding et al. 2020)	Mouse	Widespread α-synuclein inclusion pathology, no GCIs	Various degrees of motor impairment and autonomic dysfunction	Recapitulate the prion-like spreading of MSA-derived α-synuclein; Require a transgenic background or viral-mediated α-synuclein overexpression (no inclusion pathology in wild-type mice) No GCIs
Tg(SNCA*A53T + / +)Nbm mouse inoculated with MSA-derived α-synuclein (Woerman et al. 2019)
rAAV2/7 A53T α-synuclein overexpressing mouse inoculated with MSA-derived α-synuclein (van der Perren et al. 2020)

3-NP 3-nitropropionic acid, 6-OHDA: 6-hydroxydopamine, AAV adeno-associated virus, CG4 central glia 4, CNP cyclic nucleotide 3’-phosphodiesterase, GCI glial cytoplasmic inclusion, iPSC induced pluripotent stem cells, i.p. intra-peritoneal, i.v. intra-venous, MBP myelin basic protein, MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MSA multiple system atrophy, OPCA olivopontocerebellar atrophy, PBMC peripheral blood monocyte cells, PLP proteolipid protein, QA quinolinic acid, RBD REM sleep behavior disorder, SND striatonigral degeneration