P-Type ATPase Functions in Neurodegenerative Disorders

P-Type ATPases comprise a diverse family of membrane transporters that harness ATP hydrolysis to move ions or molecules across cellular membranes, thereby sustaining electrochemical gradients and organellar homeostasis. In the nervous system, mutations in several P-Type ATPases—most notably the P5B-ATPase ATP13A2—disrupt lysosomal acidification and polyamine export, leading to α-synuclein accumulation, impaired autophagy and proteostatic stress. Other subfamilies, including P4- and P5A-ATPases, regulate lipid translocation and metal ion balance within endoplasmic reticulum and endosomal compartments, influencing vesicle trafficking, mitochondrial function and neuronal survival. Loss of P-Type ATPase function is implicated in Parkinson’s disease, neuronal ceroid lipofuscinoses and related movement disorders. Recent structural and mechanistic insights into transport-cycle intermediates and regulatory domains have elucidated conserved principles of substrate recognition and autoinhibition. These discoveries underpin global efforts to develop small-molecule modulators that restore ATPase activity or compensate for ion and lipid transport deficits, offering promising new avenues for therapeutic intervention in neurodegenerative disease.

Research from Nature Portfolio

Recent studies have demonstrated that the Parkinson’s disease-associated ATP13A2 functions as a lysosomal H+,K+-ATPase, controlling lumenal pH and K+ gradients essential for α-synuclein degradation. Pharmacological inhibition of its H+,K+ transport activity induces lysosomal alkalinisation and promotes protein aggregation. High-resolution cryo-electron microscopy of a yeast P5B-ATPase homologue has defined three key transport-cycle conformations, revealing an electronegative cleft for polyamine binding and an autoinhibited phosphorylated state in the absence of cargo. Foundational work has also uncovered a regulatory network in which ATP13A2 loss diminishes expression of another Parkinson’s gene, SYT11, via mTORC1-mediated TFEB repression, leading to autophagy–lysosome dysfunction and neurodegenerative phenotypes.

P-Type ATPase Functions in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in p-type atpase functions in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

P-Type ATPase: A membrane enzyme family that couples ATP hydrolysis to the active transport of ions or molecules across cellular membranes.

Lysosomal acidification: The process of maintaining a low internal pH within lysosomes to activate degradative enzymes and support cellular clearance.

Polyamines: Small polycationic compounds (such as putrescine, spermidine and spermine) involved in cell growth, autophagy regulation and neuroprotection.

α-Synuclein: A neuronal presynaptic protein prone to misfolding and aggregation into Lewy bodies, central to Parkinson’s disease pathology.

Autophagy–lysosome pathway: A cellular degradation system whereby autophagosomes sequester damaged proteins or organelles and fuse with lysosomes for recycling.

Flippase: An enzyme that translocates specific lipids from one leaflet of a bilayer membrane to the other, modulating membrane curvature and trafficking.

References

1. Polyamines in Parkinson's Disease: Balancing Between Neurotoxicity and Neuroprotection. Annual Review of Biochemistry (2023).
2. The Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nature Communications (2016).
3. Structure and transport mechanism of P5B-ATPases. Nature Communications (2021).
4. Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase. Nature Communications (2023).
5. The Yeast P5 Type ATPase, Spf1, Regulates Manganese Transport into the Endoplasmic Reticulum. PLOS ONE (2013).
6. Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders. Frontiers in Molecular Neuroscience (2014).
7. Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export. Acta Neuropathologica (2020).