Immunotherapy Blocking Microglial FcγR Prevents Neuron Loss in Parkinson’s Illness

Parkinson’s illness (PD) is outlined by the progressive lack of dopaminergic neurons within the substantia nigra, however the organic forces that push these neurons towards degeneration stay solely partly understood. Microglia—the mind’s resident immune cells—have lengthy been implicated on this course of. They develop into reactive early in illness, cluster round weak neurons, and launch inflammatory elements. But the exact set off that converts microglia from protecting sentinels into energetic contributors in neuronal destruction has remained elusive.

A brand new examine revealed in npj Parkinson’s Illness, “Microglial low-affinity FcγR mediates the phagocytic elimination of dopaminergic neurons in Parkinson’s illness degeneration,” presents a mechanistic rationalization. Researchers on the Institut de Neurociències of the Universitat Autònoma de Barcelona (INc‑UAB) and the UAB division of biochemistry and molecular biology report that microglia in PD seem to get rid of dopaminergic neurons via an Fc gamma receptor (FcγR)–pushed phagocytic program—and that blocking this receptor with immunotherapy can stop neuron loss in illness fashions.

The group started by inspecting postmortem mind tissue from PD sufferers. As anticipated, the substantia nigra contained a excessive proportion of reactive microglia, per power neuroinflammation. However a extra putting discovering emerged: these reactive microglia expressed elevated ranges of low‑affinity Fcγ receptors (CD16 and CD32). These receptors usually assist immune cells establish broken or antibody‑tagged targets for clearance. In PD, nonetheless, the researchers suggest that FcγRs could also be misidentifying nonetheless‑viable dopaminergic neurons as particles.

This sample was mirrored within the MPTP mouse mannequin of PD, the place microglia additionally upregulated FcγRs and bodily engaged degenerating dopaminergic neurons. Prior work from the identical group had proven that microglia make direct physique‑to‑physique contact with weak neurons earlier than their disappearance, suggesting an energetic phagocytic course of moderately than passive degeneration.

To check whether or not FcγRs had been driving this elimination, the researchers turned to each in vitro and in vivo techniques. In co‑cultures modeling an interferon‑γ–pushed inflammatory atmosphere, microglia readily engulfed dopaminergic cells—however this phagocytosis was sharply diminished when FcγRs had been blocked with neutralizing antibodies. In parallel, inhibiting Cdc42, a cytoskeletal regulator downstream of FcγR signaling, additionally prevented microglia from forming the actin‑wealthy “phagocytic cup” required to engulf neurons.

“Lastly, passive immunotherapy utilizing CD16/32 neutralizing monoclonal antibodies in MPTP-treated mice protected DA neurons from elimination, suggesting a novel and viable potential therapeutic technique for PD,” the authors wrote. This intervention preserved dopaminergic neurons even below situations of intense neuroinflammation.

“What is especially fascinating is that in animal and mobile fashions of the illness, blocking Fc gamma receptors with immunotherapy, in addition to pharmacologically inhibiting Cdc42, considerably diminished the elimination of dopaminergic neurons, preserving them even below situations of intense neuroinflammation,” mentioned corresponding writer Carlos Barcia, PhD, from UAB.

Collectively, the findings place FcγR‑mediated phagocytosis as a central mechanism of dopaminergic neuron loss in PD—and spotlight microglial FcγR as a promising immunotherapeutic goal. Whereas the work stays preclinical, it opens a brand new translational path: as an alternative of attempting to rescue neurons after they degenerate, future therapies may stop microglia from mistakenly “consuming” them within the first place.