Multiple System Atrophy: Many Lessons from the Transcriptome

Abstract

Multiple system atrophy (MSA) is a complex, multifactorial, debilitating neurodegenerative disease that is often misdiagnosed and misunderstood. MSA has two subclasses, MSA-P and MSA-C, defined by the dominance of parkinsonism or cerebellar dysfunction in the earlier stages of disease, coupled with dysautonomia. This distinction between subclasses becomes largely redundant as the disease progresses. Aggregation of α-synuclein is a clinical marker used to confirm MSA diagnoses, which can only be performed postmortem. Transcriptome profiling provides in-depth information about the diseased state and can contribute to further understanding of MSA, enabling easier and more rapid diagnosis as well as contributing to improving the quality of life of people with MSA. Currently, there is no method of diagnosing MSA with certainty, and there is no cure for this disease. This review provides an update on current advances in investigations of molecular pathology of MSA with particular focus on perturbation of individual gene expression and MSA transcriptome.

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

“…Two different clinical subtypes have been described based on the predominating motor features noted during the early stages of the disease: the MSA-P subtype (dominated by parkinsonism) and the MSA-C subtype (dominated by cerebellar ataxia). However, in the later stages of the disease, the phenotypic characteristics of both subtypes are typically noted in the patient [18]. A definitive diagnosis of MSA is obtained through autopsy confirmation of a high density of α-synuclein-containing protein aggregates, known as glial cytoplasmic inclusion (GCI) bodies, in oligodendrocytes along with striatonigral degeneration and/or olivopontocerebellar atrophy [10,52,67].…”

“…Additionally, the toxic α-synuclein species may spread to neurons in other synaptically-connected brain regions in a prion-like fashion. The lack of effective oligodendrocyte support for the local neurons, and the neuronal effects of the α-synuclein inclusions, eventually results in axonal dysfunction, neuronal cell death, and a reactive astrogliosis [18].…”

Transcriptional profiling of Multiple System Atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

“…Two different clinical subtypes have been described based on the predominating motor features noted during the early stages of the disease: the MSA-P subtype (dominated by parkinsonism) and the MSA-C subtype (dominated by cerebellar ataxia). However, in the later stages of the disease, the phenotypic characteristics of both subtypes are typically noted in the patient [16]. A definitive diagnosis of MSA is obtained through autopsy confirmation of a high density of α -synuclein-containing protein aggregates, known as glial cytoplasmic inclusion (GCI) bodies, in oligodendrocytes along with striatonigral degeneration and/or olivopontocerebellar atrophy (Bhidayasiri and Ling, 2008;Papp et al, 1989;Stefanova et al, 2009).…”

“…Additionally, the toxic αsynuclein species may spread to neurons in other synaptically-connected brain regions in a prion-like fashion. The lack of effective oligodendrocyte support for the local neurons, and the neuronal effects of the α-synuclein inclusions, eventually results in axonal dysfunction, neuronal cell death, and a reactive astrogliosis [16].…”

Laser microdissection method for neurodegenerative diseases

“…MSA-C typically involves patients previously known as OPCA classical. Both phenotypes are usually observed in patients at the later stage of the disease [58][59][60][61][62][63][64].…”