Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases

Nanna Møller Jensen; Zagorka Vitic; Mia R. Antorini; Tobias Bruun Viftrup; Laura Parkkinen; Poul Henning Jensen

doi:10.1007/s00401-025-02871-w

Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases

Nanna Møller Jensen^*, Zagorka Vitic, Mia R. Antorini, Tobias Bruun Viftrup, Laura Parkkinen^*, Poul Henning Jensen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

4 Citations (Scopus)

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.

Original language	English
Article number	41
Journal	Acta Neuropathologica
Volume	149
Issue	1
Number of pages	16
ISSN	0001-6322
DOIs	https://doi.org/10.1007/s00401-025-02871-w
Publication status	Published - Jun 2025

Keywords

Lewy body disease
LRRK2
Neurodegeneration
Non-inclusion pathology
Proximity ligation assay
α-Synuclein

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title = "Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases",

abstract = "Lewy body diseases are common neurodegenerative diseases, including Parkinson{\textquoteright}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.",

keywords = "Lewy body disease, LRRK2, Neurodegeneration, Non-inclusion pathology, Proximity ligation assay, α-Synuclein",

author = "Jensen, \{Nanna M{\o}ller\} and Zagorka Vitic and Antorini, \{Mia R.\} and Viftrup, \{Tobias Bruun\} and Laura Parkkinen and Jensen, \{Poul Henning\}",

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doi = "10.1007/s00401-025-02871-w",

language = "English",

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journal = "Acta Neuropathologica",

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T1 - Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases

AU - Jensen, Nanna Møller

AU - Vitic, Zagorka

AU - Antorini, Mia R.

AU - Viftrup, Tobias Bruun

AU - Parkkinen, Laura

AU - Jensen, Poul Henning

N1 - Publisher Copyright: © The Author(s) 2025.

PY - 2025/6

Y1 - 2025/6

N2 - 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.

AB - 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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KW - Non-inclusion pathology

KW - Proximity ligation assay

KW - α-Synuclein

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DO - 10.1007/s00401-025-02871-w

M3 - Journal article

C2 - 40314782

AN - SCOPUS:105003935184

SN - 0001-6322

VL - 149

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 1

M1 - 41

ER -

Abundant non-inclusion α-synuclein pathology in Lewy body-negative LRRK2-mutant cases

Abstract

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