Log In

Forgot Password?

OR

Not a member? Continue as a nonmember.

Become a Member

By becoming a member of the AAN, you can receive exclusive information to help you at every stage of your career. Benefits include:

Join Now See All Benefits

Loading... please wait

Abstract Details

Mitochondrial Dysfunction in Neuron-Derived Extracellular Vesicles and Brain Tissues of FXTAS Patients
Aging, Dementia, Cognitive, and Behavioral Neurology
ES2 - Emerging Science 2 (6:00 PM-6:06 PM)
006

FXTAS is caused by premutations of the fragile X mental retardation 1 (FMR1) gene with 55-200 CGG repeats. Premutation carriers are at increased risk of developing intention tremor, ataxia, parkinsonism, and cognitive impairment with age. Mitochondrial dysfunction contributes to FXTAS pathogenesis.

The objective of this study was to develop biomarkers reflecting mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) using plasma neuron-derived extracellular vesicles (NDEVs) from living patients and controls, and assess their biological validity in frozen brain tissues.

We isolated plasma NDEVs by immunoaffinity capture targeting L1CAM from 8 FXTAS patients (stage 1-4) and 4 male controls and measured the quantity and activity of complex IV and V (also termed ATP synthase). Additionally, we processed frozen cerebellar and frontal cortex samples from a separate cohort of 8 FXTAS patients (stage 4-5) and 9 male controls and evaluated the same measures.

In NDEVs, FXTAS patients compared to controls had lower activity of complex IV (0.027 vs. 0.046 AU, p = 0.02) and ATP synthase (0.037 vs. 0.062 AU, p = 0.046), but also higher ATP synthase quantity (0.0024 vs. 0.0016 AU, p = 0.03). ATP synthase activity was negatively correlated with FXTAS stage (r = -0.613, p = 0.045). The cerebellum of FXTAS patients compared to controls had lower complex IV quantity (2.004 vs 9.226 AU, p = 0.005) and activity (0.191 vs. 0.604 AU, p = 0.01); and lower ATP synthase quantity (7.852 vs. 19.953 AU, p = 0.037). No differences were observed for frontal cortex.

Quantitative and functional abnormalities in mitochondrial electron transport chain and ATP production are manifest in plasma NDEVs of FXTAS patients and correlate with disease severity. These abnormalities may be predominantly attributable to the cerebellum. Plasma NDEVs may provide biomarkers for FXTAS prediction and monitoring.

Authors/Disclosures
Apostolos Manolopoulos, MD
PRESENTER
The institution of Dr. Manolopoulos has received research support from National Institute on Aging (NIA/NIH).
Pamela J. Yao, PhD (NIH/NIA) Dr. Yao has nothing to disclose.
David Hessl (MIND Institute, University of California Davis) The institution of Prof. Hessl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zynerba Pharmaceuticals. The institution of Prof. Hessl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Tetra Therapeutics. The institution of Prof. Hessl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Healx.
Susan M. Rivera, PhD (UC Davis) The institution of Dr. Rivera has received research support from National Institutes of Health. Dr. Rivera has received personal compensation in the range of $500-$4,999 for serving as a Grant Reviewer with NIH. Dr. Rivera has received personal compensation in the range of $0-$499 for serving as a Public Member of Interagency Autism Coordinating Committee with U.S. Department of Health and Human Services .
Randi Hagerman Randi Hagerman has received publishing royalties from a publication relating to health care.
Veronica Martinez Cerdeno, PhD Dr. Martinez Cerdeno has nothing to disclose.
Flora Tassone Flora Tassone has nothing to disclose.
Dimitrios Kapogiannis, MD The institution of Dr. Kapogiannis has received research support from National Institute on Aging (NIA/NIH).