by FGF from photoreceptors (Fig. 5) (3). Thus,
photoreceptors independently regulate the ability
of wrapping glia to induce differentiation in the
lamina as well as the timing and pattern of this
induction. All wrapping glia–driven rescues of
the rho3 mutant generated all lamina neuron
subtypes (fig. S4 and table S1). However, this was
not the case for lamina-driven rescues of rho3,
which produced aberrant subtypes while sometimes lacking others (fig. S4 and table S1). By
signaling through glia, photoreceptors may be
translating a homogeneous cue (EGF) into a
spatiotemporally graded one, which appears essential for diversifying (L1 to L4) neuronal fates.
(iii) Glial cells may be well suited for integrating
sparse cues to interpret them into stronger or
more robust signals (31). Thus, by amplifying
cues from photoreceptors, glia may help reduce
noise or variability of the signaling outcome.
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We thank M. Amoyel, G. Odell, K. Menon, S. Kunes, and current
and former laboratory members for insightful comments
and suggestions. We thank B. Shilo, L. Partridge, E. Hafen,
P. Léopold, Y. N. Jan, and E. Bach for reagents. This work was
supported by NIH grant EY13012 to C.D.; V.M.F. was supported
by Natural Sciences and Engineering Research Council of
Canada and Canadian Institutes of Health Research–Banting
postdoctoral fellowships. The supplementary materials contain
Materials and Methods
Figs. S1 to S4
Tables S1 and S2
Movies S1 to S3
27 March 2017; accepted 27 June 2017
b2-Adrenoreceptor is a regulator of
the a-synuclein gene driving risk
of Parkinson’s disease
Shuchi Mittal,1,2,3 Kjetil Bjørnevik,4,5 Doo Soon Im,6 Adrian Flierl,7 Xianjun Dong,1,2,3
Joseph J. Locascio,1,8 Kristine M. Abo,1 Elizabeth Long,1 Ming Jin,2,3 Bing Xu,9
Yang K. Xiang,9 Jean-Christophe Rochet,10 Anders Engeland,4,11 Patrizia Rizzu,12
Peter Heutink,12 Tim Bartels,2,3 Dennis J. Selkoe,2,3 Barbara J. Caldarone,3,13
Marcie A. Glicksman,13 Vikram Khurana,2,3,14 Birgitt Schüle,7 David S. Park,6
Trond Riise,4,5 Clemens R. Scherzer1,2,3*
Copy number mutations implicate excess production of a-synuclein as a possibly causative
factor in Parkinson’s disease (PD). Using an unbiased screen targeting endogenous gene
expression, we discovered that the b2-adrenoreceptor (b2AR) is a regulator of the a-synuclein
gene (SNCA). b2AR ligands modulate SNCA transcription through histone 3 lysine 27
acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians,
the b2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with
reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76).
Conversely, a b2AR antagonist correlated with increased risk. b2AR activation protected
model mice and patient-derived cells. Thus, b2AR is linked to transcription of a-synuclein and
risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.
The brains of most patients with Parkinson’s disease (PD) are riddled with intracellular accumulations of a-synuclein protein known as Lewy bodies. Triplication or duplication of the wild-type a-synuclein gene (SNCA)
locus is sufficient to cause familial PD (1, 2). In
these patients, copies of functionally normal SNCA
mRNA and a-synuclein protein are increased by
about 50 to 100% (2, 3). Even smaller increases in
a-synuclein transcription may play an analogous
role in patients with sporadic disease carrying
potential regulatory variants in this gene (4).
Traditionally, drug development in PD has
focused on clearance of a-synuclein protein, blockade of its transformation into toxic species, or
amelioration of its downstream consequences.
In contrast, we hypothesized that chemical com-
pounds designed to reduce the transcription of
the SNCA gene could make it possible to prevent
or slow down the disease process in selected
patients, but this idea lacked a druggable target.
Regulation of SNCA expression appears to include
GATA transcription factor occupancy of evolu-
tionarily conserved enhancers in intronic regions
of SNCA (5) and, possibly, the NGF (nerve growth
factor) and bFGF (basic fibroblast growth factor)
pathways (6), methylation (7), and microRNAs
(8). However, none of these candidates can be
easily targeted by available medicines.
Drug screen targeting endogenous SNCA
expression identifies b2AR agonists
We developed a high-throughput gene expression
assay for endogenous human SNCA expression
Fig. 5. A signaling relay from photoreceptors
to glia to lamina precursors instructs lamina
differentiation. Model: Photoreceptors secrete
EGF and FGF, which activate EGFR and FGFR,
respectively, in wrapping glia. EGFR activation
is required for glial expression of Ilps, which
activate InR and MAPK in lamina precursors
leading to L1 to L4 differentiation. FGFR signaling
regulates glia morphogenesis and process
extension into the brain (3) and therefore
indirectly regulates the timing and patterning
of L1 to L4 differentiation.