Papp-Lantos inclusions and the pathogenesis of multiple system atrophy: an update.

Multiple systemic atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder of undetermined aetiology characterized by a distinctive oligodendrogliopathy with argyrophilic glial cytoplasmic inclusions (GCIs) and selective neurodegeneration. GCIs or Papp-Lantos inclusions, described more than 20 years ago, are now accepted as the hallmarks for the definite neuropathological diagnosis of MSA and suggested to play a central role in the pathogenesis of this disorder. GCIs are composed of hyperphosphorylated alpha-synuclein (alphaSyn), ubiquitin, LRRK2 (leucin-rich repeat serine/threonine-protein) and many other proteins, suggesting that MSA represents an invariable synucleinopathy of non-neuronal type, a specific form of proteinopathies. The origin of alphaSyn deposition in GCIs is not yet fully understood, but recent findings of dysregulation in the metabolism of myelin basic protein (MBP) and p25alpha, a central nervous system-specific protein, also called TPPP (tubulin polymerization promoting protein), strengthened the working model of MSA as a primary glial disorder and may explain frequent alterations of myelin in MSA. However, it is unknown whether these changes represent an early event or myelin dysregulation occurs further downstream in MSA pathogenesis. The association between polymorphisms at the SNCA gene locus and the risk for developing MSA also points to a primary role of alphaSyn in its pathogenesis, while in a MBP promoter-driven alphaSyn transgenic mouse model gliosis accompanied the neurodegenerative process originating in oligodendrocytes. Because alphaSyn represents a major component in both oligodendroglial and neuronal inclusions in MSA, some authors suggested both a primary oligodendrogliopathy and a neuronal synucleinopathy, but current biomolecular data and animal models support a crucial role of the Papp-Lantos inclusions and of aberrant alphaSyn accumulation as their main constituent, causing oligodendroglial pathology, myelin disruption and, finally, neuronal degeneration in MSA. The relationship between oligodendrocytes involved by Papp-Lantos inclusions and those in degenerating neurons in the course of MSA needs further elucidation.