Research Highlights

Science Photo Library

Credit: SCIEPRO/
in brief
N E U R O D E G E N E R AT I V E D I S E A S E NEUROLOGICAL DISEASE
Lysosomal channel regulates PD pathology
Lysosomal function plays a central role in neuronal homeostasis
and has been linked to Parkinson disease (PD). Now, Wie et al.
Targeting phagocytes in
have identified a growth factor-​activated, kinase-​gated, lysoso-
mal K+ channel (lysoKGF) composed of a pore-​forming protein,
progressive MS
TMEM175, and AKT, which may be an attractive therapeutic
target for PD. In HEK293T cells and knock-​in mouse neurons, Therapeutic options for the Further in vivo calcium imaging
common TMEM175 variants linked to increased or decreased progressive stage of multiple scle- in the mouse model suggested spine
PD risk were associated with loss or gain of function of the
rosis (MS) are limited, leading to loss is induced in inflamed grey
lysoKGF channel, respectively. In mice, lysoKGF deficiency led
to accelerated spreading of pathogenic α-​synuclein, loss of accumulating disability and cognitive matter by local calcium accumula­
dopaminergic neurons and impaired motor function. decline. Now, a study published in tions. In support of this concept,
Original article Wie, J. et al. A growth-​factor-activated lysosomal K+ channel Nature Neuroscience reports that a buffering extracellular calcium in
regulates Parkinson’s pathology. Nature https://doi.org/10.1038/s41586-021-03185-z small-​molecule phagocyte inhibitor cortical MS lesions in vivo helped
(2021)
protects against synapse loss in a to prevent synapse loss.
A N T I B A C T E R I A L AG E N T S mouse model of progressive MS, Next, the researchers sought
highlighting a promising avenue to determine the cell types that
Mechanism mediating methylenomycin production for translational research. are responsible for stripping the
The production of methylenomycin antibiotics by Actinobacteria MS is an autoimmune disease of synapses. Confocal 3D reconstruc­
is initiated by the binding of 2-​alkyl-4-​hydroxymethylfuran- the central nervous system that usu- tion of brain tissue from mice that
3-​carboxylic acid (AHFCA) hormones (the methylenomycin
furans (MMFs)) to the TetR family transcriptional repressor ally begins with intermittent bouts had genetically labelled phago­
MmfR, which is proposed to induce DNA release and enable of neuroinflammation that affect the cytic cells stained for synaptic
methylenomycin biosynthetic gene transcription. By solving white matter, followed by a progres- and lysosomal markers pointed
the x-​ray crystal structure of an MmfR–AHFCA complex and the sive phase of neuro­degeneration with to microglia and infiltrating
cryo-​EM structure of the MmfR–DNA complex, in combination cortical grey matter involvement. monocyte-​derived macrophages.
with studies using mutant MmfR proteins and AHFCA analogues, Progressive MS is much less well Last, Jafari et al. blocked phago-
Zhou et al. uncovered the molecular basis for hormone
understood than the relapsing– cyte activation in the mouse model
recognition and the mechanism of DNA release. Such findings
could be exploited for improved antibiotic production and remitting phase, which has hampered with a recently developed inhibitor
discovery. drug discovery for this disease stage. of colony-​stimulating factor 1 recep-
Original article Zhou, S. et al. Molecular basis for control of antibiotic production by In the current study, Jafari et al. tor (CSF1R). Low-​dose, systemic
a bacterial hormone. Nature https://doi.org/10.1038/s41586-021-03195-x (2021) used a recently developed model of administration of this compound
progressive MS in which mice immu- during cortical lesion formation
D R U G D E S I GN
nized against myelin oligodendrocyte rescued synapse pathology through
Understanding dopamine receptor signalling glycoprotein (a standard MS model) a mechanism involving reduced acti-
The dopamine G protein-coupled receptors — composed of receive injections of proinflammatory vation of microglia and diminished
the D1-like (including D1R and D5R) and D2-like receptors cytokines into the cortex. These mice recruitment of macrophages.
(including D2R, D3R, and D4R), which signal through the develop cortical lesions that recapit- “Our current model induces
stimulatory Gs protein and inhibitory Gi/o protein, respectively — ulate the grey matter pathology of an acute inflammation in the grey
represent key therapeutic targets for neurological syndromes,
cardiovascular disorders and kidney diseases. Two papers progressive MS. matter, which is well suited to study
have now solved the cryo-EM structures of several activated Using confocal imaging and induction and recovery mechanisms,
dopamine receptor complexes, providing vital information electron microscopy, the investigators but ultimately these mechanisms
for future drug discovery and design. Zhuang et al. present showed that there was widespread fail in progressive MS patients,”
four cryo-EM structures of agonist-bound human dopamine synapse loss in the cortex, similar notes Martin Kerschensteiner, one
receptors: three structures of D1R–Gs complexes, with the to that seen in the human disease, of the study leads. “One important
pan-dopamine agonist apomorphine (a widely used PD drug)
or with the D1R/D5R-selective catechol-based agonists
and spine loss preferentially affected future direction will be to define
SKF81297 and SKF83959; and one structure of the D2R–Gi excitatory synapses. Consistent the mechanisms that prevent
complex with the D2R/D3R agonist bromocriptine (another PD with a shift to inhibitory signalling, grey matter inflammation from
drug). Meanwhile, Xiao et al. present five cryo-EM structures of in vivo calcium imaging showed resolving and induce progressive
human D1R–Gs in complex with three catechol-based agonists reduced calcium transients inflammatory damage.”
(the antihypertensive drug fenoldopam and the synthetic (a measure of neuronal activity)
full agonists A-77636 and SKF83959), a non-catechol agonist Katie Kingwell
in cortical projection neurons,
PW0464 and a positive allosteric modulator for endogenous
dopamine, LY3154207. The structures, in combination with indicating neuronal silencing. Original article Jafari, M. et al. Phagocyte-​
mediated synapse removal in cortical
mutagenesis studies, provide structural insight into dopamine Loss of synapses and neuronal neuroinflammation is promoted by local calcium
receptor ligand recognition, activation, allosteric regulation activity was transient, recovering accumulation. Nat. Neurosci. https://doi.org/
10.1038/s41593-020-00780-7 (2021)
and G protein coupling specificity. to baseline after 2 weeks, although Related article Faissner, S. et al. Progressive
Original articles Zhuang, Y. et al. Structural insights into the human D1 and D2 this might not occur in the chronic multiple sclerosis: from pathophysiology to
dopamine receptor signaling complexes. Cell https://doi.org/10.1016/j.cell.2021.01.027
(2021) | Xiao, P. et al. Ligand recognition and allosteric regulation of DRD1-Gs signaling
inflammatory setting of MS in therapeutic strategies. Nat. Rev. Drug Discov. 18,
905–922 (2019)
complexes. Cell https://doi.org/10.1016/j.cell.2021.01.028 (2021) humans.

178 | MARCH 2021 | volume 20 www.nature.com/nrd

0123456789();: