Alpha‐Synuclein
            Oligomers and Neurofilament Light Chain in Spinal Fluid Differentiate Multiple System Atrophy from Lewy Body Synucleinopathies

Alpha-synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are a class of neurodegenerative diseases. A diagnosis may be challenging because clinical symptoms partially overlap, and there is currently no reliable diagnostic test available. Therefore, we aimed to identify a suitable marker protein in cerebrospinal fluid (CSF) to distinguish either between different types of alpha-synucleinopathies or between alpha-synucleinopathies and controls. In this study, the regulation of different marker protein candidates, such as alpha-synuclein (a-Syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (tau) in different types of alpha-synucleinopathies, had been analyzed by using an ultrasensitive test system called single-molecule array (SIMOA). Interestingly, we observed that CSF-NfL was significantly elevated in patients with DLB and MSA compared to patients with PD or control donors. To differentiate between groups, receiver operating characteristic (ROC) curve analysis resulted in a very good diagnostic accuracy as indicated by the area under the curve (AUC) values of 0.87–0.92 for CSF-NfL. Furthermore, we observed that GFAP and tau were slightly increased either in DLB or MSA, while a-Syn levels remained unregulated. Our study suggests NfL as a promising marker to discriminate between different types of alpha-synucleinopathies or between DLB/MSA and controls.

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Neurofilament Light Chain Predicts Disease Severity and Progression in Multiple System Atrophy

Movement Disorders ◽

10.1002/mds.28847 ◽

2021 ◽

Author(s):

Lingyu Zhang ◽

Bei Cao ◽

Yanbing Hou ◽

Xiaojing Gu ◽

Qianqian Wei ◽

...

Keyword(s):

Multiple System Atrophy ◽

Disease Severity ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light

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Longitudinal correlation between neurofilament light chain and UMSARS in Multiple System Atrophy

Clinical Neurology and Neurosurgery ◽

10.1016/j.clineuro.2020.105924 ◽

2020 ◽

Vol 195 ◽

pp. 105924

Author(s):

Carla Palleis ◽

Estrella Morenas-Rodriguez ◽

Francisco Jesús Martínez Murcia ◽

Armin Giese ◽

Brigitte Nuscher ◽

...

Keyword(s):

Multiple System Atrophy ◽

Light Chain ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Longitudinal Correlation

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Alpha‐Synuclein Oligomers and Neurofilament Light Chain Predict Phenoconversion of Pure Autonomic Failure

Annals of Neurology ◽

10.1002/ana.26089 ◽

2021 ◽

Author(s):

Wolfgang Singer ◽

Ann M. Schmeichel ◽

Mohammad Shahnawaz ◽

James D. Schmelzer ◽

David M. Sletten ◽

...

Keyword(s):

Light Chain ◽

Autonomic Failure ◽

Alpha Synuclein ◽

Pure Autonomic Failure ◽

Neurofilament Light Chain ◽

Neurofilament Light

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Microglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures

Molecular Neurodegeneration ◽

10.1186/s13024-021-00471-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Melanie Barth ◽

Mehtap Bacioglu ◽

Niklas Schwarz ◽

Renata Novotny ◽

Janine Brandes ◽

...

Keyword(s):

Human Brain ◽

Light Chain ◽

Culture Medium ◽

Alpha Synuclein ◽

Human Antibody ◽

Neurofilament Light Chain ◽

Intact Mouse ◽

Neurofilament Light ◽

Adult Human

Abstract Background Proteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression. Methods Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed. Results To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2–3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture’s genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions. Conclusion The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.

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