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Comment
. 2021 Mar 3;144(2):e15.
doi: 10.1093/brain/awaa368.

BMP5/7 protect dopaminergic neurons in an α-synuclein mouse model of Parkinson's disease

Zagorka Vitic  1 , Hazem Safory  2 , Vukasin M Jovanovic  3 , Yael Sarusi  1 , Alexandra Stavsky  1 , Joy Kahn  1 , Alona Kuzmina  4 , Lilah Toker  5   6 , Daniel Gitler  1 , Ran Taube  4 , Roland H Friedel  7 , Simone Engelender  2 , Claude Brodski  1
Affiliations
Comment

BMP5/7 protect dopaminergic neurons in an α-synuclein mouse model of Parkinson's disease

Zagorka Vitic et al. Brain. .
No abstract available

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Figures

Figure 1
Figure 1
BMP5/7 prevent A53T α-synuclein-induced substantia nigra neuronal loss, gliosis and ameliorate associated motor impairment in a Parkinson’s disease mouse model. (A, B and E–J) Representative micrographs and corresponding quantification of the substantia nigra (SN) injected with EGFP expressing vector (control), substantia nigra injected with A53T α-synuclein expressing vector (α-syn) and substantia nigra injected with A53T α-synuclein expressing vector together with striatal BMP5/7 expressing vector (α-syn + BMP5/7). (A and B) The number of TH+ neurons was decreased by A53T α-synuclein overexpression (P = 0.0178). BMP5/7 treatment prevents the decrease in the number of TH+ neurons (P = 0.0017) (Control, n = 7; α-syn, n = 18; α-syn+ BMP5/7, n = 5). (C and D) The immunofluorescence signal of striatal TH+ fibres is reduced following A53T α-synuclein overexpression (P = 0.0081) and increased by adding BMP5/7 (P = 0.0289) (Control, n = 6; α-syn, n = 7; α-syn+ BMP5/7, n = 5). (E and F) The total neuronal number as assessed by NeuN+ cells is decreased by A53T α-synuclein overexpression (P = 0.0010) and is increased after BMP5/7 treatment (P = 0.0391) (n = 3 per group). (G and H) α-Synuclein overexpression leads to an increase in the number of IBA1+ microglia cells (P = 0.0010), which is prevented by BMP5/7 treatment (P = 0.0003). (I and J) The number of GFAP+ activated astroglia cells show a trend towards an increase after α-synuclein overexpression (P = 0.1005). BMP5/7 significantly reduce the number of GFAP+ cells (P = 0.0092) (n = 3 per group). (K) α-Synuclein overexpression leads to motor impairments as indicated by the increase in the percentage of ipsilateral paw use in the Cylinder Test (P = 0.0004), which is ameliorated by BMP5/7 treatment (P = 0.0032). (L and M) α-Synuclein overexpression causes motor impairments also in the Pole Test as indicated by increased turning time (P = 0.0017) and total time (P = 0.0089). BMP5/7 significantly reduced the turning time (P = 0.0115) and the total time in the Pole Test (P = 0.0374) (Control, n = 7; α-syn, n = 18; α-syn+ BMP5/7, n = 5). Scale bar in A = 100 µm; C = 500 µm; E, G, and I = 50 µm. The data in graphs represent the mean ± standard error of the mean (SEM). *P < 0.05, **P < 0.01, ***P < 0.001 Fisher’s LSD post hoc test, after significant one-way ANOVA.
Figure 2
Figure 2
The BMP/SMAD signalling pathway modulates α-synuclein accumulation and is attenuated in Parkinson’s disease post-mortem brains. (A, B, E and F) Representative micrographs and corresponding quantification of the substantia nigra (SN) injected with EGFP expressing vector (control), substantia nigra injected with A53T α-synuclein expressing vector (α-syn) and substantia nigra injected with A53T α-synuclein expressing vector together with striatal BMP5/7 expressing vector (α-syn + BMP5/7). (A) Immunofluorescence staining of TH (top), α-synuclein (middle) and double immunolabelling of substantia nigra DA neurons (bottom). (E) A53T α-synuclein overexpression leads to α-synuclein accumulation in TH+ neurons (P = 0.0150), which is attenuated in BMP5/7 treated animals (P = 0.0015). Fisher’s LSD post hoc test, after significant one-way ANOVA (Control, n = 7; α-syn, n = 11; α-syn+ BMP5/7, n = 5). (B) Representative micrographs of immunohistochemical staining of p-S129 α-synuclein of the ventral midbrain with the injected side on the right and the contralateral control side on the left. The right column shows higher magnification of the injected side. (F) In controls, p-S129 α-synuclein-positive cells are undetected, whereas there are abundant p-S129 α-synuclein-positive cells in the injected side (set to 100 in the bar graph). The number of p-S129 α-synuclein-positive cells was significantly reduced by BMP5/7 treatment. Unpaired two-tailed Student’s t-test (P = 0.0031) (n = 5 per group). (C and D) Representative micrographs of the substantia nigra (in C and D) and the cortex and olfactory bulb (in D) of wild-type (WT) controls and of Smad1Nes mice in which Smad1 is excised in neurons. (C) Immunofluorescence of TH (top), α-synuclein (middle) and double immunolabelling of substantia nigra DA neurons (bottom) and (G and H) quantification. (G and H) Smad1Nes mutants showed an increased number of TH+/α-synuclein+ cells (P = 0.0211) associated with a reduced number of TH+ substantia nigra neurons (P = 0.0086). Unpaired two-tailed Student’s t-test (n = 3 per group). (D) Immunohistochemistry visualizing aggregated α-synuclein after proteinase K treatment. In contrast to controls that show no aggregates, Smad1Nes mutants show α-synuclein aggregates in the substantia nigra, cortex, and olfactory bulb (OB) (n = 3 per group). (I) Homogenates prepared from substantia nigra of Parkinson’s disease and control patients were probed with anti-SMAD6 antibody (left). Graph depicts SMAD6 levels normalized to LDH (right). Substantia nigra of four Parkinson’s disease patients and four aged-matched controls (Parkinson’s UK Brain Bank) were analysed in three independent experiments. Unpaired two-tailed Student’s t-test (P = 0.0285). Scale bar in A and B = 50 µm; B (insets) = 500 µm; C and D = 100 µm; The data in graphs represent mean ± SEM. Two-tailed unpaired Student’s t-test *P < 0.05, **P < 0.01. Fisher’s LSD post hoc test, after significant one-way ANOVA *P < 0.05, **P < 0.01.
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