Towards translational therapies for multiple system atrophy

Abstract

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiopathogenesis manifesting with autonomic failure, parkinsonism, and ataxia in any combination. The underlying neuropathology affects central autonomic, striatonigral and olivopontocerebellar pathways and it is associated with distinctive glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) that contain aggregates of α-synuclein. Current treatment options are very limited and mainly focused on symptomatic relief, whereas disease modifying options are lacking. Despite extensive testing, no neuroprotective drug treatment has been identified up to now; however, a neurorestorative approach utilizing autologous mesenchymal stem cells has shown remarkable beneficial effects in the cerebellar variant of MSA. Here, we review the progress made over the last decade in defining pathogenic targets in MSA and summarize insights gained from candidate disease-modifying interventions that have utilized a variety of well-established preclinical MSA models. We also discuss the current limitations that our field faces and suggest solutions for possible approaches in cause-directed therapies of MSA.

Keywords: Alpha-synuclein; Multiple system atrophy; Neurodegeneration; Olivopontocerebellar atrophy; Striatonigral degeneration.

Fig. 1

Neuropathology underlying MSA-P, MSA-C and autonomic failure in MSA. Striatonigral degeneration is the underlying pathology of MSA-P, olivopontocerebellar atrophy occurs in MSA-C and degeneration of autonomic brainstem nuclei plays a role for characteristic autonomic failure in MSA patients. SND, striatonigral degeneration; OPCA, olivopontocerebellar atrophy; SCN, suprachiasmatic nucleus; PVN, paraventricular nucleus; LC, locus coeruleus; VML, ventrolateral medulla; DMV, dorsal motor nucleus of the vagus; NA, nucleus ambiguus; IML, intermediolateral column of the thoracic spinal cord; LDT, laterodorsal tegmental nucleus; PPT, pedunculopontine tegmental nucleus; PAG, periaqueductal gray.

Fig. 2

Possible pathological α-Syn-spreading and accumulation mechanism leading to neurodegeneration. (A) Healthy neuron, oligodendrocyte, microglia and astrocyte, p25α mainly located in the myelinating oligodendroglial processes, monomeric α-Syn present in presynaptic nerve terminals. (B) Relocalisation of p25α from the processes to the soma, inclusion formation and swelling of the oligodendroglial soma. (C) Oligomeric α-Syn accumulation in the oligodendroglial cytoplasm, the exact source of α-Syn remains to be investigated. Possible hypotheses include exocytosed α-Syn from neurons and uptake into oligodendrocytes by cell-to-cell propagation or upregulation of α-Syn expression in oligodendrocytes themselves. In addition, axonal α-Syn may be taken up by the dysfunctional oligodendroglial myelin compartment. (D) α-Syn aggregates form insoluble half-moon shaped GCIs characteristic for the disease. (E) Disruption of trophic support (e.g. GDNF), mitochondrial failure, increased production of reactive oxygen species (ROS) and proteasomal dysfunction occur. (F) Oligodendrocytes suffer from severe distress and will eventually degrade. (G) Activation of micro/astroglial cells by cytokines released from the damaged oligodendrocytes, proposed secondary neuronal loss potentially due to lack of trophic support, ROS production, proteasomal failure and pro-inflammatory environment.

Fig. 3

Biomarker-supported early diagnosis of MSA: a pre-requisite for successful trial intervention.