α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease

Kundlik Gadhave; Enquan Xu; Ning Wang; Xiaodi Zhang; Jacob Deyell; Jun Yang; Anthony Wang; Youngjae Cha; Ramhari Kumbhar; Haiqing Liu; Lili Niu; Rong Chen; Shu Zhang; Catherine C Bakker; Lingtao Jin; Yajie Liang; Mingyao Ying; Valina L Dawson; Ted M Dawson; Liana S Rosenthal; Xiaobo Mao

doi:10.1101/2024.10.22.619694

α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease

bioRxiv [Preprint]. 2024 Oct 24:2024.10.22.619694. doi: 10.1101/2024.10.22.619694.

Authors

Kundlik Gadhave^{1

2}, Enquan Xu^{1

2}, Ning Wang^{1

2}, Xiaodi Zhang^{1

2}, Jacob Deyell^{1

2}, Jun Yang^{1

2}, Anthony Wang^{1

2}, Youngjae Cha^{1

2}, Ramhari Kumbhar^{1

2}, Haiqing Liu^{1

2}, Lili Niu^{1

2}, Rong Chen^{1

2}, Shu Zhang^{1

2}, Catherine C Bakker², Lingtao Jin³, Yajie Liang⁴, Mingyao Ying^{2

5}, Valina L Dawson^{1

2

6

7}, Ted M Dawson^{1

2

7

8

9}, Liana S Rosenthal², Xiaobo Mao^{1

2

9

10}

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
⁴ Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA.
⁶ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 USA.
⁷ Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁸ Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
⁹ Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.

Abstract

α-Synuclein (α-syn) strains can serve as discriminators between Parkinson's disease (PD) from other α-synucleinopathies. The relationship between α-syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of α-syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct α-syn strains in PD patients correlating to their level of cognitive impairment. This study presents evidence that individuals with PD have different α-syn strains that change in accordance with their cognitive status and highlights the potential of α-syn strain dynamics to guide future diagnosis, management, and stratification of PD patients.

Keywords: SAA; cognitive impairment; strain; α-synuclein.

Publication types

Preprint

Abstract

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