Activin A inhibits MPTP and LPS-induced increases in inflammatory cell populations and loss of dopamine neurons in the mouse midbrain in Vivo

© 2017 Stayte et al. Parkinson's disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor β superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson's disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson's disease

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus

Idiopathic congenital nystagmus (ICN) is characterised by involuntary, periodic, predominantly horizontal, oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 ICN singleton cases (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina suggesting a specific role in the control of eye movement and gaze stability

Activin A protects against 6-OHDA induced cell loss.

<p>(A) Experimental timeline detailing pump implantation, unilateral injection of 6-OHDA or ascorbic acid (sham), and tissue collection. (B) Stereological quantification of TH-immunoreactive neurons in SNpc demonstrates activin A protects dopaminergic neurons against 6-OHDA toxicity. (C) Stereological quantification of NeuN-immunoreactive neurons in SNpc demonstrates activin A protects total neuron numbers against 6-OHDA induced toxicity. All values represent the mean ± standard error of the mean (SEM). *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001. Sham + vehicle n = 4, sham + activin A n = 6, 6-OHDA + vehicle n = 7, 6-OHDA + activin A n = 7.</p

Time-dependent dopamine cell loss induced by 6-OHDA.

<p>(A) Representative images of TH-immunoreactive neurons in the SNpc. (B) Stereological quantification revealed a significant and progressive loss of dopaminergic cell numbers at 1, 2, and 3 weeks following unilateral injection of 6-OHDA or ascorbic acid (sham). All values represent the mean ± standard error of the mean (SEM) *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001 (compared to sham controls), ##<i>p</i><0.01, ###<i>p</i><0.001. N = 3 per group. Scale bar represents 200 μm.</p

Time-dependent nigral cell loss induced by 6-OHDA.

<p>(A) Representative images of NeuN-immunoreactive neurons in the SNpc. (B) Stereological quantification revealed a significant and progressive loss of total cell numbers at 1, 2, and 3 weeks following unilateral injection of 6-OHDA or ascorbic acid (sham). All values represent the mean ± standard error of the mean (SEM) *<i>p</i><0.05 **<i>p</i><0.01, ***<i>p</i><0.001 (compared to sham controls), #<i>p</i><0.05, ###<i>p</i><0.001. N = 3 per group. Scale bar represents 200 μm.</p

Activin A does not restore striatal catecholamine in 6-OHDA lesioned animals.

<p>HPLC-ECD quantification of striatal tissue revealed no significant effect of activin A on (A) DA, (B) DOPAC or (C) HVA levels following 6-OHDA compared to vehicle controls or the catabolism of DA to HVA (D). Sham = ascorbic acid. All values represent the mean ± standard error of the mean (SEM). *<i>p</i><0.05, **<i>p</i><0.01, ***<i>p</i><0.001. Sham + vehicle n = 7, sham + activin A n = 7, 6-OHDA + vehicle n = 9, 6-OHDA + activin A n = 8.</p