ArticleActa neuropathologica2025
Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases.
Article in Acta neuropathologica, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Addressing the Challenges of Translating LRRK2 Biology into Disease-Modifying Therapies: The LRRK2 Investigative Therapeutics Exchange Initiative.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Selective loss of primary cilia and neurotrophic signaling in G51D α-synuclein mice highlights a common pathway to Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Co- and Multi-Pathologies in Parkinson's Disease: An International Parkinson and Movement Disorder Society Scientific Issues Committee Review.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Pathology and Genetics in a Global Cohort of Parkinsonian Disorders.JAMA neurology · 2026Article
- Spatial multi-omics identifies early synaptic pruning and context-specific dopaminergic vulnerability in synucleinopathies.Nature communications · 2026Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- Seeing Invisible Oligomers: Rethinking α-Synuclein Pathology Through Proximity Ligation Assay.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Neuropathology in genetic Parkinson's disease: a focused review of pathological and clinical findings.Journal of neural transmission (Vienna, Austria : 1996) · 2026Review
- Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation.Cell reports · 2026Article
- Lewy Bodies Are Not Associated With Neuronal or Synaptic Loss in Dementia With Lewy Bodies.Neuropathology and applied neurobiology · 2026Article
- Review
- Discordance of Dopaminergic Dysfunction and Subcortical Atrophy by α-Synuclein Status in Sporadic and Genetic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- LRRK2 and GBA1 in Lewy body diseases: neuropathological subtypes at opposite ends of a spectrum?Molecular neurodegeneration · 2026Review
- Focused Ultrasound for the Treatment of Circuit and Molecular Pathology in Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Therapeutic potential of sulforaphane in neurodegenerative diseases: mechanistic Insights into Nrf2, NF-κB, TrkB, SIRT1, MAPK, and JAK/STAT signalling pathways.Molecular biology reports · 2026Review
- Pathology and genetics in a global cohort of Parkinsonian Disorders.medRxiv : the preprint server for health sciences · 2026Article
- Higher-molecular-weight a-synuclein oligomers are increased in the brain cytosol of patients with dementia with Lewy bodies.NPJ Parkinson's disease · 2026Article
- α-Synuclein in Lewy Body Diseases: Progress, Remaining Challenges and Future Perspectives.Expert reviews in molecular medicine · 2026Review
- LRRK2 as a Potential Disease-Modifying Target in Sporadic Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2026Review
- Seed amplification of released alpha-synuclein strains reveals genotype-specific differences in Parkinson's disease neurons.Frontiers in aging neuroscience · 2026Article
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6 authors.
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Abstract
Lewy body diseases are common neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies, which lead to both motor and non-motor symptoms. They are neuropathologically characterized by loss of neuromelanized neurons in the substantia nigra pars compacta and α-synuclein-immunopositive inclusions (Lewy bodies) in several types of neurons in the brain. A fraction of monogenic PD cases, however, represent a conundrum, as they can present with clinical Lewy body disease but do not have Lewy bodies upon neuropathological examination. For LRRK2, the presence or absence of Lewy bodies is not related to any specific mutation in the gene and different clinical presentation and neuropathology can be present even in the same family. Here, we present the first evidence of widespread α-synuclein accumulation detected with proximity ligation assay (PLA) using the MJFR14-6-4-2 antibody in six Lewy body-negative LRRK2 cases and compare the levels with five patients with neuropathologically verified Lewy body disease and six healthy controls. We show that non-inclusion aggregated α-synuclein in the form of particulate PLA signal is dominant in the LRRK2 cases, while both Lewy-like and particulate PLA signal is found in late-stage Lewy body disease. Furthermore, LRRK2 cases displayed prominent particulate PLA signal in pontocerebellar tracts and inferior olivary nuclei in the brainstem, which was not seen in idiopathic Lewy body disease cases. These results suggest that Lewy-body negative LRRK2-related PD is not associated with a lack of α-synuclein aggregation in neurons but rather a deficiency in the formation of inclusions.
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