ATP and NAD+ Deficiency in Parkinson’s Disease

Abstract

The goal of this study is to identify a signature of bioenergetic and functional markers in the muscles of individuals with Parkinson’s disease (PD). Quantitative physiological properties of in vivo hand muscle (FDI, first dorsal interosseus) and leg muscle (TA, Tibialis Anterior) of older individuals with PD were compared to historical age/gender-matched controls (N = 30). Magnetic resonance spectroscopy and imaging (MRS) were used to assess in vivo mitochondrial and cell energetic dysfunction, including maximum mitochondrial ATP production (ATPmax), NAD concentrations linked to energy/stress pathways, and muscle size. Muscle function was measured via a single muscle fatigue test. TA ATPmax and NAD levels were significantly lower in the PD cohort compared to controls (ATPmax: 0.66 mM/s ± 0.03 vs. 0.76 ± 0.02; NAD: 0.75 mM ± 0.05 vs. 0.91 ± 0.04). Muscle endurance and specific force were also lower in both hand and leg muscles in the PD subjects. Exploratory analyses of mitochondrial markers and individual symptoms suggested that higher ATPmax was associated with a greater sense of motivation and engagement and less REM sleep behavior disorder (RBD). ATPmax was not associated with clinical severity or individual symptom(s), years since diagnosis, or quality of life. Results from this pilot study contribute to a growing body of evidence that PD is not a brain disease, but a systemic metabolic syndrome with disrupted cellular energetics and function in peripheral tissues. The significant impairment of both mitochondrial ATP production and resting metabolite levels in the TA muscles of the PD patients suggests that skeletal muscle mitochondrial function may be an important tool for mechanistic understanding and clinical application in PD patients. This study looked at individuals with mid-stage PD; future research should evaluate whether the observed metabolic perturbations in muscle dysfunction occur in the early stages of the disease and whether they have value as theragnostic biomarkers.

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson’s disease in an Egyptian cohort

“…We found lower levels of NADH, nicotinamide, nicotinic acid (quinolinate metabolites, and the precursors and metabolites of NAD+ and NADP+) in P than in C. This reduction in NAD levels may have a role in the neurotoxicity in PD. These findings are aligned with previous research; for example, one study found that NAD levels were significantly lower in the muscles of 30 PD patients compared to age-matched controls ( Mischley et al, 2023 ), while a clinical trial phase I study tested the effect of oral administration of nicotinamide riboside (NR) in 30 PD patients, and found that NR increases the levels of NAD, stimulates the transcriptional upregulation of the processes related to mitochondrial, lysosomal, and proteasomal activities in skeletal muscles and blood cells, and decrease the inflammatory cytokines ( Brakedal et al, 2022 ). Another study found that NR increased NAD, which led to not only ameliorating the mitochondrial functions in induced pluripotent stem cells isolated from PD patients but also preventing age-related dopaminergic neuronal loss and motor deficits in fly models of GBA-PD ( Schöndorf et al, 2018 ).…”

Association of metabolic syndrome and its components with Parkinson’s disease: a cross-sectional study

“…Numerous pathogenic processes, including IR, oxidative stress, immunology, and inflammation, may overlap between MetS and PD [ 8 , 33 , 34 ]. This overlap suggests that PD should be treated as a metabolic disease [ 35 , 36 ]. IR is a key factor in type 2 diabetes and is now recognized as an important mechanism in the association between DM and PD.…”

Direct single-molecule detection of CoA-SH and ATP by the membrane proteins TMEM120A and TMEM120B

“…As critical components in cellular metabolism, COA-SH and ATP are strongly linked to cell growth, death, and energy provision. 19,20 Abnormal levels of these molecules in the body closely correlate with various diseases, 21 such as cardiovascular diseases, 22 Parkinson's disease, 23 and Alzheimer's disease. 24 Therefore, the development of point-of-care testing (POCT) sensors capable of directly and accurately detecting COA-SH and ATP holds significant importance.…”