Progressive striatonigral degeneration in a transgenic mouse model of multiple system atrophy: translational implications for interventional therapies.

Abstract

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder characterized by widespread oligodendroglial cytoplasmic inclusions of filamentous α-synuclein, and neuronal loss in autonomic centres, basal ganglia and cerebellar circuits. It has been suggested that primary oligodendroglial α-synucleinopathy may represent a trigger in the pathogenesis of MSA, but the mechanisms underlying selective vulnerability and disease progression are unclear. The post-mortem analysis of MSA brains provides a static final picture of the disease neuropathology, but gives no clear indication on the sequence of pathogenic events in MSA. Therefore, alternative methods are needed to address these issues. We investigated selective vulnerability and disease progression in the transgenic PLP-α-syn mouse model of MSA characterized by targeted oligodendroglial α-synuclein overexpression aiming to provide a neuropathological correlate of motor deterioration. We show progressive motor deficits that emerge at 6 months of age and deteriorate up to 18 months of follow-up. The motor phenotype was associated with dopaminergic cell loss in the substantia nigra pars compacta at 6 months, followed by loss of striatal dopaminergic terminals and DARPP32-positive medium sized projection neurons at 12 months. Olivopontocerebellar motor loops remained spared in the PLP-α-syn model of MSA. These findings replicate progressive striatonigral degeneration underlying Parkinson-variant MSA. The initiation of the degenerative process was linked to an increase of soluble oligomeric α-synuclein species between 2 and 6 months. Early region-specific α-synuclein-associated activation profile of microglia was found in MSA substantia nigra. The role of abnormal neuroinflammatory signalling in disease progression was further supported by increased levels of CD68, CCL3, CCL5 and M-CSF with a peak in aged PLP-α-syn mice. In summary, transgenic PLP-α-syn mice show a distinctive oligodendroglial α-synucleinopathy that is associated with progressive striatonigral degeneration linked to abnormal neuroinflammatory response. The model provides a relevant tool for preclinical therapeutic target discovery for human Parkinson-variant MSA.

• Authors: Violetta Refolo, Francesco Bez, Alexia Polissidis, Daniela Kuzdas-Wood, Edith Sturm, Martina Kamaratou, Werner Poewe, Leonidas Stefanis, M Angela Cenci, Marina Romero-Ramos, Gregor K Wenning, Nadia Stefanova
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 6 Issue 1 Pg. 2 (01 03 2018) ISSN: 2051-5960 [Electronic] England
• PMID: 29298733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aif1 protein, mouse
• Antigens, CD
• Calcium-Binding Proteins
• Microfilament Proteins
• Myelin Proteolipid Protein
• Nerve Tissue Proteins
• alpha-Synuclein

Topics

• Age Factors
• Analysis of Variance
• Animals
• Antigens, CD (metabolism)
• Calcium-Binding Proteins (metabolism)
• Disease Models, Animal
• Gene Expression Regulation (genetics)
• Humans
• Mice
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Microglia (metabolism, pathology)
• Microscopy, Confocal
• Movement Disorders (etiology)
• Multiple System Atrophy (cerebrospinal fluid, complications, genetics)
• Muscle Strength (genetics)
• Myelin Proteolipid Protein (genetics, metabolism)
• Nerve Tissue Proteins (metabolism)
• Postural Balance (genetics)
• Sensation Disorders (etiology)
• Striatonigral Degeneration (etiology)
• alpha-Synuclein (genetics, metabolism)