Undisclosed ATP13A2 modulator / Merck (MSD) - LARVOL DELTA

Deciphering Spastic Ataxia: Clinical and Genetic Profiles. (PubMed, Neurol Genet) - "The most frequent diagnoses were ARSACS (17.4%), ATX-SYNE1 (6.5%), ATX-ANO10, HSP/ATX-KIF1C, HSP/ATX-PGN, HSP-ZFYVE26, MxMD-ATP13A2, and ATX/HSP-KCNA2 (4.3% each)...Spastic ataxia represented a clinically and genetically distinct subgroup within HCA, marked by recessive inheritance, large genetic heterogeneity, and more severe motor impairment. Greater awareness of its heterogeneous presentations and progressive disability over time is crucial for timely diagnosis, genetic counseling, and development of tailored management strategies for these patients."

Journal • Ataxia • CNS Disorders • Genetic Disorders • Movement Disorders • SYNE1

Homology Modeling of Type-P5 ATPases from the Malaria Parasite: Insight into Their Functions and Evolution, and Implications About the Effect and Role of Intrinsically Disordered Protein Structure. (PubMed, Pathogens) - "In this study, Spf1, a subtype-P5A ATPase of yeast, and ATP13A2, a subtype-P5B ATPase of humans, were used as templates to extensively characterize the sequences and structural features of haemosporidian type-P5 ATPases...In contrast, the subtype-P5B ATPases of the malaria parasite are not likely to be polyamine transporters in lysosomes, as have been described in fungi and metazoans. This suggests that subtype-P5B ATPases have undergone lineage-specific divergence in regard to their function(s)."

Journal • Infectious Disease • Malaria

Kufor-Rakeb Syndrome in a Guatemalan Patient With an ATP13A2 Gene Pathogenic Variant: A Case Report. (PubMed, Case Rep Genet) - "Genetic testing identified a homozygous pathogenic variant in ATP13A2. This report underscores the importance of recognizing KRS in diverse populations and of using gene-based testing to guide diagnosis, counseling, and multidisciplinary supportive care."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

C-Myc Indirectly Controls ATP13A2 Levels via HIF-1α Activation. (PubMed, J Neurochem) - "Prussian blue analysis indicated corresponding changes in intracellular iron accumulation with the temporal alterations in ATP13A2 expression. Our findings indicate that c-Myc indirectly causes an increased ATP13A2 expression by increasing HIF1α accumulation."

Journal • CNS Disorders • Movement Disorders • Oncology • Parkinson's Disease • HIF1A • MYC

The genetics of autosomal recessive early-onset Parkinson's disease. (PubMed, Curr Opin Neurobiol) - "Two phenotypes can be distinguished: typical EOPD, which progresses slowly (PRKN, PINK1 and DJ-1), and atypical PD, often associated with additional symptoms (ATP13A2, FBXO7, DNAJC6, VPS13C, SYNJ1, PLA2G6)...Five new genes have been reported to contribute to EOPD associated with various neurological signs (PTPA, DAGLB, PSMF1, EPG5, SGIP1). Small molecules targeting PRKN dysfunctions are expected to enter clinical trials in the coming years, paving the way for targeted therapies in EOPD."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • PTPA • VPS13C

Phenotypic characterization of an Atp13a2 knockout rat model of Parkinson's disease. (PubMed, NPJ Parkinsons Dis) - "Finally, we tested whether inducing pathology by viral-mediated overexpression of human α-synuclein or human tyrosinase exacerbated the onset or extent of pathological changes. This Atp13a2 KO rat model could help better understand autophagy in PD pathogenesis and open new therapeutic validation opportunities."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • Tyrosinase

ATP13A2 is involved in intracellular polyamine transport in lung epithelial cells. (PubMed, FEBS Open Bio) - "Overexpression of ATP13A2 caused a moderate increase in total cellular polyamine content, whereas ATP13A2 knockdown resulted in a decrease in cellular polyamine levels. These findings provide novel information regarding the cellular function of ATP13A2 in lungs and contribute to our understanding of cellular polyamine transport systems."

Journal

Aav-human a53t-mutated synuclein disrupts nigro-striatal system in mice (Neuroscience 2025) - "In addition, analysis of the newly identified Parkinson's disease (PD)-relevant biomarkers—NOD2, OGA, TMEM175, TRPML1, TFEB and ATP13A2—is currently ongoing. In summary, the AAV-human A53T α-syn mouse model recapitulates several core features of PD and enables studying A53T α-syn-related pathologies and downstream signaling. The model might be further valuable for the analysis of molecular mechanisms underlying synucleinopathies and pave the way for the development of novel therapeutic interventions."

Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease • CD8 • TFEB

Lysosomal Polyamine Sequestration Drives Epigenetic and Neurotoxic Changes in Parkinson's Disease Astrocytes (Neuroscience 2025) - "Grant Support ASAP-024297 Loss-of-function (LOF) variants in ATP13A2 cause juvenile-onset Parkinson's disease (PD), a rare and severe form with early onset of motor and cognitive symptoms...This work identifies new therapeutic targets and provides an innovative strategy to model brain aging in vitro by manipulating polyamine biology. Together, these results offer key insight into how metabolic and epigenetic changes in astrocytes drive early neurodegeneration and highlight the potential for targeting polyamine pathways to mitigate age-related and genetic forms of PD."

CNS Disorders • Movement Disorders • Parkinson's Disease

Overexpression of ATP13A2 rescues lysosomal and metabolomic disruptions in GBA-Parkinson's induced pluripotent stem cell derived dopamine neurons (Neuroscience 2025) - "Overall, our findings indicate that the loss of ATP13A2 in GBA-PD leads to disruption of lysosomal and polyamine homeostasis. Restoration of lysosomal and polyamine dysfunction by ATP13A2 overexpression highlights the therapeutic potential of ATP13A2 for GBA-PD."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

Nanotechnology-based approach to restore lysosomal function in Parkinson's disease (Neuroscience 2025) - "We then tested the effect of this therapeutic strategy in wild-type or ALP-deficient cell culture, but also in vivo on wild-type mice and ATP13A2 KO rats, with different routes of administration (i.e., intracerebral, retro-orbital, and intranasal injections). These data suggest that strategies enhancing or restoring lysosomal-mediated degradation appear as a tantalizing neuroprotective/disease-modifying therapeutic strategy and would be of significant therapeutic interest for PD."

CNS Disorders • Movement Disorders • Parkinson's Disease

Sphingolipid Metabolism Dysregulation Drives Immune Microenvironment Remodeling and Predicts Prognosis in Bladder Cancer. (PubMed, Int J Genomics) - "Key findings revealed that SM dysregulation correlated with poor clinical outcomes and eight pivotal prognostic genes (ATP13A2, PCSK2, NR2F1, GSDMB, NFASC, NTF3, LGALS4, and SREBF1) were identified...These results suggest that SM dysregulation may drive immunomodulatory changes in BLCA microenvironments, offering mechanistic insights into tumor immune evasion. This study provides a novel biomarker tool for risk stratification and highlights SM pathways as potential therapeutic targets for BLCA patients with immune microenvironment dysregulation."

Journal • Bladder Cancer • Genito-urinary Cancer • Metabolic Disorders • Oncology • Solid Tumor • CD8 • LGALS4 • NR2F1 • NTF3

Rare Variants, Copy Number Variations, and Heritability Estimates in a Pilot Cohort of Egyptians with Parkinson's Disease (MDS Congress 2025) - "CNV analysis revealed a PD-specific duplication in 1p36.33-q44, spanning PD-associated risk genes (DJ1, VPS13D, ATP13A2, PINK1, DNAJC6)... This pilot study offers novel insights into the genetic architecture of PD in Egypt, highlighting potential population-specific genetic contributions. While these findings require validation in larger studies, they contribute to reducing disparities in global PD genetics research."

CNS Disorders • Movement Disorders • Parkinson's Disease • ADH1C • GIGYF2 • LRRK2 • VPS13D

Genetic Analysis of Parkinson's Disease in Crete (MDS Congress 2025) - "In total, 27 pathogenic/likely pathogenic variants were identified, including 25 heterozygous carriers of nine autosomal-dominant variants [GBA1 (n=17); LRRK2 (n=5); SNCA (n=1); GCH1 (n=2)], two homozygous carriers of two autosomal-recessive variants [(PINK1 (n=1); FIG4 (n=1)], and 34 heterozygous carriers of 16 autosomal-recessive variants [PNPLA6 (n=9); ATP13A2 (n=7); POLG (n=6); PRKN (n=5); PINK1 (n=4); SPG7 (n=2); PARK7 (n=1); GCH1 (n=1)]... In a large sample from Crete, 8.6% of cases were attributed to genetic PD, while an additional 10.8% were heterozygous carriers of recessive pathogenic/likely pathogenic variants. Although these figures fall at the higher end of the genetic PD spectrum, many variants remain unidentified and warrant further investigation."

CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • SNCA

Genotype-Phenotype Relations in Neurodegeneration with Brain Iron Accumulation (NBIA) Genes: MDSGene Systematic Review (MDS Congress 2025) - " Following MDSGene literature search and data extraction protocols, we systematically abstracted and summarized the clinical and genetic features of reported individuals with NBIA linked to the following genes: PANK2, C9orf12, COASY, DCAF17, FAHN, FTL, ATP13A2, WDR45, REPS1, CRAT, and CP... We present the most comprehensive review of existing literature regarding genotype-phenotype relationships for all known NBIA genes. Findings from this study will be instrumental in addressing research and clinical practice gaps. Our systematic review will be made publicly available in the mdsgene.org domain in the future."

Review • CNS Disorders • Movement Disorders • FTL

NOVEL MUTATION IN ATP13A2 KUFOR-RAKEB SYNDROME (PARK9) IN AN ALGERIAN FAMILY (WCN 2025) - "This is the first Algerian PARK9 family with a new mutation and new clinical signs such as deviation of the uvula, fasciculations and non-response to L dopa."

CNS Disorders • Depression • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry

Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson's Disease Mutations. (PubMed, bioRxiv) - "Global gene expression and pre-mRNA splicing patterns were analyzed in midbrain cultures carrying pathogenic PD mutations in the PRKN , SNCA , LRRK2 , PINK1 , DNAJC6 , FBXO7 , SYNJ1 , DJ1, VPS13C , ATP13A2 and GBA1 genes...Importantly, we have also shown that subsets of these splicing changes overlap with changes found in PD patient postmortem brains. Mutation-specific pre-mRNA isoforms may function as both diagnostic biomarkers for familial PD-associated genotypes and promising therapeutic targets."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2 • SNCA • VPS13C

Lysosomal polyamine storage upon ATP13A2 loss impairs β-glucocerebrosidase via altered lysosomal pH and electrostatic hydrolase-lipid interactions. (PubMed, Cell Rep) - "A liposome-based GCase assay utilizing physiological substrates demonstrated dose-dependent inhibition of BMP-stimulated GCase activity by polyamines, in part via a pH-independent, electrostatics-based mechanism. Therefore, excess polyamine compromises lysosomes by disrupting pH and electrostatic interactions between GCase and BMP that enable efficient substrate hydrolysis, potentially clarifying pathogenic mechanisms and suggesting convergence on PD-relevant pathways."

Journal • CNS Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Rare Diseases

Case Report: Novel ATP13A2 pathogenic variants associated with early-onset parkinsonism and a mini-review. (PubMed, Front Genet) - "Additionally, we reviewed the previously published cases, focusing on early signs and symptoms, clinical evolution and response to therapy. To our knowledge, this is the only work that groups all reported KRS patients and compares their clinical and molecular features."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Parkinson's Disease

Prognostic and Biological Roles of Parkinson's Disease-Associated Genes in Cancer. (PubMed, Mov Disord) - "This study suggests that PD and cancer may be connected through shared biological pathways, some overlapping with cancer hallmarks, and highlights the need for future mechanistic and functional studies to clarify the role of PD genes in cancer biology."

Journal • Brain Cancer • CNS Disorders • Gastrointestinal Cancer • Melanoma • Movement Disorders • Oncology • Parkinson's Disease • Solid Tumor • LRRK2 • SNCA • TP53

Phenotype Differences Between ATP13A2 Heterozygous and Knockout Mice Across Aging. (PubMed, Int J Mol Sci) - "In contrast, Het mice showed impairments in cognitive function and an age-related increase in αSyn in the brain. These results indicate potentially different pathological mechanisms when ATP13A2 is reduced compared to when it is knocked out and may have important implications for disease modification in synucleinopathies including PD."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Movement Disorders • Parkinson's Disease • GFAP

Computational association in parkinson's disease SNPs with brain structural and functional alterations. (PubMed, Neurogenetics) - "SNCA, LRRK2, NURR1, ATP13A2, GSK3B, Parkin, PINK1, DJ-1, and UCHL1are the major genes involved and play a crucial role in the regulatory mechanisms and progression of PD...Subsequently, molecular dynamics simulations were performed on the identified compound. These results provide new insights into the genetic variants linked to PD and contribute to the exploration of future research directions in the field of PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Rare Diseases • GSK3B • LRRK2 • NR4A2 • SNCA

Phenotypic variability in ATP13A2 mutations-First Report of SPG78 from India. (PubMed, J Mov Disord) - No abstract available

Journal

ATP13A2 IS ESSENTIAL FOR THE MAINTENANCE OF HEMATOPOIETIC STEM CELLS UNDER STRESS (EHA 2025) - "Knockout of the ATP13a2 gene affects the number of bone marrow hematopoietic stem/progenitor cells under stress, indicating impaired hematopoietic function."

Clinical

The genetics of motor neuron disease in New Zealand. (PubMed, J Neurol Sci) - "Variants of interest were found in 14 participants with the splicing variants DCTN1:c.279+1G>C and ATP13A2:c.2412G>A, p.(Lys804=) subject to further study. Notably, 48.4% of pathogenic variants were in pre-symptomatic, unaffected individuals with family history, highlighting the importance of offering cascade testing and symptom surveillance for families, particularly as gene-specific treatments emerge."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • DCTN1