Parkinson’s disease (PD) is traditionally described as a dopaminergic neurodegenerative disorder driven by α-synuclein aggregation and selective neuronal loss in the substantia nigra pars compacta. While this characterization captures the core clinical and pathological features, it does not fully explain disease initiation and progression. Converging evidence from human genetics, cellular and structural biology, and systems neuroscience now supports a unified framework in which PD results from the progressive erosion of mitochondrial resilience. Here, mitochondrial resilience denotes the capacity of neuronal mitochondrial networks to withstand stress and recover bioenergetic and cellular homeostasis through coordinated quality control, metabolic adaptation, and organelle communication. Rare, high-impact monogenic mutations in
PINK1
,
PRKN
(encoding Parkin), PARK7 (
DJ-1)
,
LRRK2
, and
SNCA
, along with common risk variants identified in genome-wide association studies, converge on interconnected pathways that govern mitochondrial quality control, bioenergetics, organelle dynamics, and cellular stress responses. These vulnerabilities are most pronounced in the highly energetic dopaminergic neurons of the substantia nigra, where sustained calcium cycling, high bioenergetic demand, and environmental stressors increase cellular susceptibility. Research has moved beyond early observations of respiratory chain impairment and oxidative stress to reveal context-specific disruptions in PINK1/Parkin-mediated mitophagy, lysosomal trafficking, mitochondrial-derived vesicle dynamics, and neuroimmune signaling. This integrated framework reframes PD as a disorder of impaired cellular maintenance rather than solely a consequence of late-stage degenerative processes. It provides a translational shift from mechanism-based biomarkers to early detection of mitochondrial failure and supports therapeutic strategies aimed at restoring mitochondrial function and resilience, offering a direct route to disease-modifying neuroprotection in PD and potentially other neurodegenerative disorders.
Oscar Arias-Carrión, Magdalena Guerra-Crespo, L. O. Soto-Rojas et al.· Frontiers in Pharmacology· 0 citations
Leucine-rich repeat kinase 2 (LRRK2) has emerged as a central molecular node linking genetic risk, membrane trafficking, lysosomal homeostasis, and immune signalling in Parkinson’s disease (PD). Rather than functioning as a conventional protein kinase, LRRK2 operates as a conformationally regulated, Rab-directed signalling machine whose activity is governed by long-range interdomain communication, membrane recruitment, and cooperative interactions with small GTPases. Converging advances in cryo-electron microscopy, quantitative phosphoproteomics, and human genetics indicate that pathogenic mutations, lysosomal stress, and pharmacological inhibitors do not simply alter catalytic output, but reshape the conformational landscape of LRRK2, biasing it toward distinct structural states with divergent cellular consequences. A defining feature of this system is the selective phosphorylation of Rab GTPases at low stoichiometry—most prominently Rab8 and Rab10—yet with disproportionate functional impact on vesicle trafficking, ciliogenesis, autophagy, and organelle positioning. The identification of Rab-directed phosphatases, particularly PPM1H, further establishes that LRRK2 signalling is governed by a dynamically balanced kinase–phosphatase circuit operating in space and time. These observations, together with emerging evidence linking LRRK2 activation to lysosomal damage and immune pathways, support a unifying hypothesis: PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis, rather than from kinase hyperactivity alone. In this review, we integrate structural, biochemical, and cellular evidence to advance this framework and discuss its implications for disease mechanisms and therapy. We highlight key unresolved challenges—including conformation-selective drug targeting, spatial control of Rab phosphorylation, and context-dependent immune–neuronal crosstalk—and propose that restoring physiological regulation of LRRK2, rather than simply inhibiting its activity, will be essential for achieving mechanism-based disease modification in Parkinson’s disease.
Oscar Arias-Carrión, Magdalena Guerra-Crespo, Daniel Ortuño-Sahagún et al.· International Journal of Mol...· 0 citations