Magnetoreceptors in Parkinson’s disease

PD is a progressive neurodegenerative disorder primarily affecting dopaminergic neurons in the substantia SNpc, resulting in characteristic motor symptoms and a wide spectrum of non-motor manifestations. Core pathological features of PD include mitochondrial dysfunction, oxidative stress, impaired proteostasis, and aggregation of α-synuclein into LBs. As outlined in earlier sections, magnetoreceptors-particularly the CRY/MagR complex-operate through radical-pair-mediated redox mechanisms and circadian regulation. In the context of PD, these pathways intersect with molecular processes that are especially critical for dopaminergic neuron survival and function [110,111].

Through their impact on spin-dependent electron transfer, CRY/MagR assemblies may indirectly shape cellular redox homeostasis. Neuronal populations with elevated energetic demands, such as dopaminergic neurons, are particularly sensitive to redox imbalance because of sustained pacemaking activity and tight coupling between mitochondrial function and calcium fluxes. Under these conditions, minor disruptions in radical-pair processes could trigger excessive ROS accumulation, thereby accelerating oxidative damage and increasing susceptibility to neurodegeneration in PD [112].

Mitochondrial dysfunction represents a central pathogenic axis in PD, particularly involving impairment of complex I activity in SNpc neurons. Redox perturbations associated with magnetoreceptor signalling may further destabilize mitochondrial electron transport, increasing electron leakage and ROS generation. Elevated ROS promotes oxidative damage to mitochondrial DNA, cardiolipin peroxidation, and depolarization of the mitochondrial membrane potential, ultimately compromising ATP synthesis and calcium buffering. These effects are especially deleterious in dopaminergic neurons, where sustained calcium-dependent firing imposes continuous bioenergetic stress [113,114].

α-synuclein aggregation is a defining pathological hallmark of PD. Oxidative modifications of α-synuclein, including methionine oxidation, tyrosine nitration, and redox-dependent conformational destabilization, enhance its propensity to misfold and form toxic oligomeric assemblies. Radical-pair-associated increases in ROS may therefore indirectly accelerate α-synuclein oligomerization and fibrillization. In addition, oxidatively modified α-synuclein exhibits increased affinity for mitochondrial membranes, where it can inhibit complex-I function and further exacerbate mitochondrial dysfunction, establishing a self-reinforcing pathogenic loop [115].

Redox-sensitive kinase and phosphatase signalling pathways provide another point of convergence between magnetoreceptor activity and PD pathology. Oxidative stress activates kinases such as GSK3β, JNK, p38 MAPK, and LRRK2, which are implicated in pathological α-synuclein phosphorylation, particularly at Ser129 a modification strongly associated with LBs formation. Concurrently, ROS-mediated inhibition of phosphatases such as PP2A prolongs aberrant phosphorylation states. Together, these processes favor sustained α-synuclein aggregation and disrupt cytoskeletal integrity and axonal transport in dopaminergic neurons [116,117].

Failure of protein quality control mechanisms further accelerates neurodegeneration in PD. Both the ubiquitin-proteasome system and the autophagy-lysosomal pathway are essential for α-synuclein clearance yet are highly sensitive to oxidative damage. Redox imbalance associated with radical-pair signalling may impair chaperone activity, lysosomal enzyme function, and mitophagy, leading to intracellular accumulation of misfolded α-synuclein. This proteostatic failure amplifies mitochondrial stress and oxidative burden, reinforcing neurodegenerative cascades [118].

Circadian dysregulation is increasingly recognized as an important contributor to PD pathophysiology. Clinical and experimental studies indicate that disturbances in circadian rhythms manifesting as fragmented sleep-wake cycles, altered melatonin secretion, and impaired diurnal regulation of dopamine synthesis and release often precede or accompany motor symptom onset. At the cellular level, circadian clock components, including CRY1 and CRY2, regulate mitochondrial bioenergetics, antioxidant gene expression, and autophagy in dopaminergic neurons. Disruption of CRY-dependent circadian signalling can therefore exacerbate oxidative stress, impair mitochondrial quality control, and reduce the efficiency of α-synuclein clearance. In the SNpc, circadian misalignment may further increase neuronal vulnerability by uncoupling energy production from intrinsic pacemaking activity [111,119].

Although direct causal evidence linking magnetoreceptor activity to PD in humans remains limited, experimental studies in model organisms demonstrate that external magnetic fields can modulate CRY-dependent redox signalling, neuronal excitability, and circadian behaviour. Collectively, these findings suggest that CRY/MagR-mediated mechanisms may intersect with mitochondrial dysfunction, oxidative stress, α-synuclein aggregation, impaired proteostasis, and circadian disruption-core processes underlying PD neurodegeneration. Further studies in mammalian and human-relevant models are required to determine whether modulation of magnetoreceptor pathways represents a meaningful contributor to disease progression or a potential target for non-invasive neuromodulatory strategies [90,120]. A summary of the key physiological roles discussed in the context of AD and PD is provided in Table 1, highlighting their potential relevance to CRY/MagR-mediated pathways in neurodegeneration.

Disease | Protein / Molecule | Physiological role | Pathological role | Interaction with CRY/MagR / magnetic fields
AD | Amyloid-β (Aβ) | Synaptic plasticity, memory, antimicrobial activity | Plaque formation, synaptic toxicity, calcium and mitochondrial dysregulation | Radical-pair-mediated ROS may enhance Aβ aggregation and tau phosphorylation
AD | Tau | Microtubule stabilization, axonal transport | Neurofibrillary tangles (NFTs), hyperphosphorylation, mitochondrial and synaptic dysfunction | Redox stress via CRY/MagR can promote tau hyperphosphorylation and aggregation
PD | α-Synuclein | Synaptic vesicle regulation, dopamine release | Lewy body formation, synaptic dysfunction, oxidative stress | ROS from radical-pair signaling may accelerate α-synuclein aggregation
PD | Dopaminergic neurons | Dopamine synthesis, pacemaking activity | Neuronal death, metabolic and oxidative stress | Highly sensitive to CRY/MagR-mediated redox perturbations, increasing vulnerability
AD & PD | Mitochondria | ATP production, calcium buffering | Dysfunction, increased ROS | CRY/MagR radical-pair activity can modulate ROS levels and mitochondrial function
AD & PD | Circadian clock (CRY1/CRY2) | Regulation of circadian rhythms, gene expression, cellular metabolism | Circadian disruption, impaired protein clearance | Directly influenced by magnetic fields through CRY/MagR, affecting neuronal metabolism and proteostasis