Multiple system atrophy: genetic risks and alpha-synuclein mutations

Abstract

Multiple system atrophy (MSA) is one of the few neurodegenerative disorders where we have a significant understanding of the clinical and pathological manifestations but where the aetiology remains almost completely unknown. Research to overcome this hurdle is gaining momentum through international research collaboration and a series of genetic and molecular discoveries in the last few years, which have advanced our knowledge of this rare synucleinopathy. In MSA, the discovery of α-synuclein pathology and glial cytoplasmic inclusions remain the most significant findings. Families with certain types of α-synuclein mutations develop diseases that mimic MSA, and the spectrum of clinical and pathological features in these families suggests a spectrum of severity, from late-onset Parkinson's disease to MSA. Nonetheless, controversies persist, such as the role of common α-synuclein variants in MSA and whether this disorder shares a common mechanism of spreading pathology with other protein misfolding neurodegenerative diseases. Here, we review these issues, specifically focusing on α-synuclein mutations.

Keywords: MSA; multiple system atrophy; neurodegenerative disorders; α-synuclein.

Figure 1.. Structural features of the alpha-synuclein monomer.

A structure of the full-length, membrane-bound form of alpha-synuclein (SNCA) protein reveals a conformation in which the N-terminal two-thirds of the protein forms a broken, amphipathic alpha-helix. This structured portion of the protein is responsible for membrane binding, and residues at the very N-terminus are essential for this process. In the nuclear magnetic resonance structure of SNCA, the negatively charged C-terminal tail remains flexible and disordered (based on Yu et al. ). The positions of point mutations associated with Parkinson’s disease are indicated with arrows and in pink. All mutations are heterozygous, except for p.A53V, which is homozygous.