Abstract
Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting α-syn modified for improved central nervous system penetration (CD5-D5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-α-syn transgenic mouse model of MSA. While the use of either CD5-D5 or lenalidomide alone had positive effects on neuroinflammation and/or α-syn accumulation in this mouse model of MSA, the combination of both approaches yielded better results than each single treatment. The combined treatment reduced astrogliosis, microgliosis, soluble and aggregated α-syn levels, and partially improved behavioral deficits in MBP-α-syn transgenic mice. These effects were associated with an activation of the Akt signaling pathway, which may mediate cytoprotective effects downstream tumor necrosis factor alpha (TNFα). These results suggest that a strategic combination of treatments may improve the therapeutic outcome in trials for MSA and related neurodegenerative disorders.
Highlights
Multiple system atrophy (MSA) is a rapidly progressive and fatal neurodegenerative disease characterized by parkinsonism, dysautonomia [5, 56], and accumulation of the protein alpha-synuclein (α-syn) within oligodendroglial cells in the form of glial cytoplasmic inclusions [16, 19] leading to neuroinflammation, demyelination and neurodegeneration [15, 25, 43, 47, 50, 57]
In the current study we explored the neuroprotective effects of the combined treatment of lenalidomide and CD5-D5 in the Myelin Basic Protein (MBP)-α-syn tg mouse model of MSA
Additional file 1: V5 immunostaining confirms the expression of the single-chain antibody CD5-D5-apolipoprotein B (ApoB). (A) Representative images of V5 immunostaining (LV-CD5-D5-ApoB tag) in the neocortex of non-tg and MBP-α-syn tg mice treated with LV-control or LV-CD5-D5-ApoB, and vehicle or lenalidomide. (B) Cell counts of V5-positive cells in in the neocortex of non-tg and MBP-α-syn tg mice treated with LV-control or LV-CD5-D5-ApoB, and vehicle or lenalidomide. (TIF 1365 kb)
Summary
Multiple system atrophy (MSA) is a rapidly progressive and fatal neurodegenerative disease characterized by parkinsonism, dysautonomia [5, 56], and accumulation of the protein alpha-synuclein (α-syn) within oligodendroglial cells in the form of glial cytoplasmic inclusions [16, 19] leading to neuroinflammation, demyelination and neurodegeneration [15, 25, 43, 47, 50, 57]. MSA is an orphan neurodegenerative disorder with no effective disease-modifying treatment, and recent clinical trials of MSA therapies have failed to meet primary endpoints [7, 23, 30, 35] These negative results were probably associated with the late diagnosis of this disorder, and treatments being initiated when α-syn accumulation and neuroinflammation are already widespread. We observed that the antidepressants fluoxetine, olanzapine and amitriptyline ameliorate neuroinflammation, and reduce the accumulation of α-syn in the Myelin Basic Protein (MBP)-α-syn transgenic (tg) mouse model of MSA [50] Another unconventional anti-inflammatory, the anticancer drug and immunomodulatory compound lenalidomide, was able to effectively reduce microgliosis and the expression of pro-inflammatory cytokines in an animal model of Parkinson’s disease (PD) [48], a disorder characterized by the accumulation of α-syn.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
