PLA2G6 Genetic Variants in Neurodegenerative Disorders

Genetic variants in PLA2G6, the gene encoding the calcium-independent phospholipase A2 group VI enzyme, underlie a spectrum of neurodegenerative disorders collectively known as PLAN (PLA2G6-associated neurodegeneration). These include infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism and autosomal recessive early-onset parkinsonism. Pathogenic changes in PLA2G6 disrupt lipid homeostasis, leading to membrane remodeling defects, mitochondrial dysfunction and elevated lipid peroxidation. Neuropathological hallmarks range from axonal spheroids and brain iron accumulation to widespread Lewy body and tau pathology, reflecting convergent pathways with idiopathic Parkinson’s disease. Clinical onset spans from infancy to late adulthood, with marked phenotypic heterogeneity even among carriers of identical variants. Owing to founder effects and consanguinity in certain populations, novel missense, in-frame deletion and splice-site mutations continue to emerge. Advances in molecular diagnostics, in silico pathogenicity prediction and patient-derived cellular models have refined diagnosis and illuminated mechanistic bridges between PLA2G6 dysfunction, impaired autophagy and dopaminergic neuron loss. Understanding these interconnections holds promise for targeted interventions, including small-molecule modulators of lipid metabolism and gene-based therapies, with potential to alter disease trajectories globally.

Research from Nature Portfolio

Recent studies in a foundational mouse model of PLA2G6 deficiency have highlighted the role of store-operated calcium signalling in neurodegeneration. Genetic or molecular disruption of PLA2G6-dependent calcium influx was shown to trigger autophagic impairment, progressive loss of nigral dopaminergic neurons and age-dependent, L-DOPA-sensitive motor deficits. This work establishes a mechanistic link between PLA2G6 variants and pathways central to idiopathic Parkinson’s disease, opening avenues for therapies aimed at restoring calcium-mediated autophagy and neuronal survival.

PLA2G6 Genetic Variants in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in pla2g6 genetic variants in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

PLA2G6: Gene encoding the calcium-independent phospholipase A2 group VI enzyme involved in membrane lipid turnover.

iPLA2β: The enzyme product of PLA2G6 that hydrolyses phospholipids to release free fatty acids.

Infantile neuroaxonal dystrophy (INAD): A severe early-onset neurodegenerative disorder characterised by axonal swelling and rapid motor regression.

Parkinsonism: A clinical syndrome defined by bradykinesia, rigidity, rest tremor and postural instability.

Genotype–phenotype correlation: Analysis of how specific genetic variants manifest as observable clinical features.

Autophagy: A cellular degradation pathway that removes damaged organelles and proteins via lysosomal recycling.

References

1. PLA2G6‐associated late‐onset parkinsonism in a Sudanese family. Annals of Clinical and Translational Neurology (2023).
2. Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients. Orphanet Journal of Rare Diseases (2023).
3. PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes. Frontiers in Neurology (2018).
4. Impairment of PARK14-dependent Ca2+ signalling is a novel determinant of Parkinson’s disease. Nature Communications (2016).
5. Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain (2015).
6. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiology of Aging (2010).